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Williams MJ, Patel HM, Halling CB, Hruska KA. The Impact of a Western Diet High in Phosphate on the CKD-MBD in an Alport Syndrome Model. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.17.633378. [PMID: 39896481 PMCID: PMC11785106 DOI: 10.1101/2025.01.17.633378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Background Chronic kidney disease - mineral bone disorder (CKD-MBD) is a syndrome that begins early in CKD, contributes to CKD-associated mortality, and includes components of FGF23 elevation, αklotho deficiency, CKD-stimulated vascular disease, and renal osteodystrophy. Hyperphosphatemia, occurring in later stages of CKD, is also driven by mechanisms of CKD-MBD, and has been shown to stimulate vascular calcification. In a mouse model of Alport CKD that is resistant to vascular calcification, we examine the effects of a high-phosphate Western-type diet on the CKD-MBD, and test whether the diet promotes induction of vascular calcification. Methods An X-linked Col4a5 deficient murine homolog of Alport Syndrome (CKD) and wild type (WT) littermates were fed an animal protein 1.2% high phosphate diet or a standard vegetable protein diet. At disease progression equivalent to CKD stage 4-5, we examined kidney histology for fibrosis, blood for BUN (marker of CKD), and markers of CKD-MBD disease progression, kidney tissue for klotho production, and aorta histology and tissue mRNA and protein analysis for vascular calcification. Results The Western high Pi diet produced hyperphosphatemia in the CKD animals compared to WT and increased plasma PTH (1880 from 110 pg / ml), FGF23 c-term (670 from 120 pg / ml), and FGF23 intact (3780 from 280 pg / ml), and reduced kidney klotho mRNA and protein (57-67% reduction) (all p < 0.01). Referenced against the CKD animals fed vegetable-based diet, the Western high phosphate-fed CKD animals showed higher levels of plasma PTH and FGF23s. In the wild-type control mice with normal renal function, Western diet produced increased PTH, intact FGF23, and reduced renal klotho (all p <0.01). Vascular smooth muscle transdifferentiation and vascular calcification was not induced by Western high phosphate diet in this model of CKD. Conclusions Our results show that a Western-style high-phosphate diet advances elements of the CKD-MBD. Renal klotho, FGF23 and PTH are affected by diet even with normal kidney function, suggesting a need for early intervention in the management of phosphate homeostasis as a component of CKD therapy. Additionally, CKD, klotho, and FGF23 all are associated with early aging. Therefore, our findings suggest that a Western high Pi diet accelerates aging and would contribute to the systemic complications of CKD - cardiac disease, osteodystrophy, and vascular disease.
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Shoji T, Mori K, Nagakura Y, Kabata D, Kuriu K, Nakatani S, Uedono H, Nagata Y, Fujii H, Imanishi Y, Morioka T, Emoto M. Associations of Cognitive Function with Serum Magnesium and Phosphate in Hemodialysis Patients: A Cross-Sectional Analysis of the Osaka Dialysis Complication Study (ODCS). Nutrients 2024; 16:3776. [PMID: 39519609 PMCID: PMC11547714 DOI: 10.3390/nu16213776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 11/01/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024] Open
Abstract
Cognitive impairment and dementia are common in patients with chronic kidney disease, including those undergoing hemodialysis. Since magnesium and phosphate play important roles in brain function and aging, alterations in these and other factors related to bone mineral disorder (MBD) may contribute to low cognitive performance in patients on hemodialysis. This cross-sectional study examined the associations between cognitive function and MBD-related factors among 1207 patients on maintenance hemodialysis. Cognitive function was assessed by the Modified Mini-Mental State examination (3MS). The exposure variables of interest were serum magnesium, phosphate, calcium, calcium-phosphate product, intact parathyroid hormone, fetuin-A, T50 calciprotein crystallization test, use of phosphate binders, use of cinacalcet, and use of vitamin D receptor activators. Multivariable-adjusted linear regression models were used to examine the associations between 3MS and each of the exposure variables independent of 13 potential non-mineral confounders. We found that lower 3MS was associated with lower serum magnesium, lower phosphate, lower calcium-phosphate product, and nonuse of phosphate binders. These results suggest that magnesium and phosphate play potentially protective roles against cognitive impairment in this population.
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Affiliation(s)
- Tetsuo Shoji
- Department of Vascular Medicine, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan;
- Vascular Science Center for Translational Research, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan;
| | - Katsuhito Mori
- Department of Nephrology, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan;
| | - Yu Nagakura
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan; (Y.N.); (S.N.); (H.U.); (Y.I.); (T.M.)
| | - Daijiro Kabata
- Center for Mathematical and Data Sciences, Kobe University, Kobe 657-8501, Japan;
- Department of Medical Statistics, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan;
| | - Kaori Kuriu
- Department of Medical Statistics, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan;
| | - Shinya Nakatani
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan; (Y.N.); (S.N.); (H.U.); (Y.I.); (T.M.)
| | - Hideki Uedono
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan; (Y.N.); (S.N.); (H.U.); (Y.I.); (T.M.)
| | - Yuki Nagata
- Department of Vascular Medicine, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan;
- Vascular Science Center for Translational Research, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan;
| | - Hisako Fujii
- Department of Health and Medical Innovation, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan;
| | - Yasuo Imanishi
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan; (Y.N.); (S.N.); (H.U.); (Y.I.); (T.M.)
| | - Tomoaki Morioka
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan; (Y.N.); (S.N.); (H.U.); (Y.I.); (T.M.)
| | - Masanori Emoto
- Vascular Science Center for Translational Research, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan;
- Department of Nephrology, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan;
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan; (Y.N.); (S.N.); (H.U.); (Y.I.); (T.M.)
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Chen X, Wei Y, Li Z, Zhou C, Fan Y. Distinct role of Klotho in long bone and craniofacial bone: skeletal development, repair and regeneration. PeerJ 2024; 12:e18269. [PMID: 39465174 PMCID: PMC11505971 DOI: 10.7717/peerj.18269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 09/17/2024] [Indexed: 10/29/2024] Open
Abstract
Bone defects are highly prevalent diseases caused by trauma, tumors, inflammation, congenital malformations and endocrine abnormalities. Ideally effective and side effect free approach to dealing with bone defects remains a clinical conundrum. Klotho is an important protein, which plays an essential role in regulating aging and mineral ion homeostasis. More recently, research revealed the function of Klotho in regulating skeleton development and regeneration. Klotho has been identified in mesenchymal stem cells, osteoblasts, osteocytes and osteoclasts in different skeleton regions. The specific function and regulatory mechanisms of Klotho in long bone and craniofacial bone vary due to their different embryonic development, ossification and cell types, which remain unclear and without conclusion. Moreover, studies have confirmed that Klotho is a multifunctional protein that can inhibit inflammation, resist cancer and regulate the endocrine system, which may further accentuate the potential of Klotho to be the ideal molecule in inducing bone restoration clinically. Besides, as an endogenous protein, Klotho has a promising potential for clinical therapy without side effects. In the current review, we summarized the specific function of Klotho in long bone and craniofacial skeleton from phenotype to cellular alternation and signaling pathway. Moreover, we illustrated the possible future clinical application for Klotho. Further research on Klotho might help to solve the existing clinical difficulties in bone healing and increase the life quality of patients with bone injury and the elderly.
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Affiliation(s)
- Xinyu Chen
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yali Wei
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Operative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zucen Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Operative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chenchen Zhou
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yi Fan
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Operative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Carmine TC. The role of age and sex in non-linear dilution adjustment of spot urine arsenic. BMC Nephrol 2024; 25:348. [PMID: 39396936 PMCID: PMC11475607 DOI: 10.1186/s12882-024-03758-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 09/13/2024] [Indexed: 10/15/2024] Open
Abstract
BACKGROUND Previous research introduced V-PFCRC as an effective spot urinary dilution adjustment method for various metal analytes, including the major environmental toxin arsenic. V-PFCRC normalizes analytes to 1 g/L creatinine (CRN) by adopting more advanced power-functional corrective equations accounting for variation in exposure level. This study expands on previous work by examining the impacts of age and sex on corrective functions. METHODS Literature review of the effects of sex and age on urinary dilution and the excretion of CRN and arsenic. Data analysis included a Data Set 1 of 5,752 urine samples and a partly overlapping Data Set 2 of 1,154 combined EDTA blood and urine samples. Both sets were classified into age bands, and the means, medians, and interquartile ranges for CRN and TWuAs in uncorrected (UC), conventionally CRN-corrected (CCRC), simple power-functional (S-PFCRC), sex-aggregated (V-PFCRC SA), and sex-differentiated V-PFCRC SD modes were compared. Correlation analyses assessed residual relationships between CRN, TWuAs, and age. V-PFCRC functions were compared across three numerically similar age groups and both sexes. The efficacy of systemic dilution adjustment error compensation was evaluated through power-functional regression analysis of residual CRN and the association between arsenic in blood and all tested urinary result modes. RESULTS Significant sex differences in UC and blood were neutralized by CCRC and reduced by V-PFCRC. Age showed a positive association with blood arsenic and TWuAs in all result modes, indicating factual increments in exposure. Sex-differentiated V-PFCRC best matched the sex-age kinetics of blood arsenic. V-PFCRC formulas varied by sex and age and appeared to reflect urinary osmolality sex-age-kinetics reported in previous research. V-PFCRC minimized residual biases of CRN on TWuAs across all age groups and sexes, demonstrating improved standardization efficacy compared to UC and CCRC arsenic. INTERPRETATION Sex differences in UC and CCRC arsenic are primarily attributable to urinary dilution and are effectively compensated by V-PFCRC. While the sex and age influence on V-PFCRC formulas align with sex- and age-specific urinary osmolality and assumed baseline vasopressor activities, their impact on correction validity for entire collectives is minimal. CONCLUSION The V-PFCRC method offers a robust correction for urinary arsenic dilution, significantly reducing systemic dilution adjustment errors. Its application in various demographic contexts enhances the accuracy of urinary biomarker assessments, benefiting clinical and epidemiological research. V-PFCRC effectively compensates for sex differences in urinary arsenic. Age-related increases in TWuAs are exposure-related and should be additionally accounted for by algebraic normalization, covariate models, or standard range adjustments.
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Wang Z, Xue H, Sun Y, Wang Q, Sun W, Zhang H. Deciphering the Biological Aging Impact on Alveolar Bone Loss: Insights From α-Klotho and Renal Function Dynamics. J Gerontol A Biol Sci Med Sci 2024; 79:glae172. [PMID: 38995226 DOI: 10.1093/gerona/glae172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Indexed: 07/13/2024] Open
Abstract
Alveolar bone loss is generally considered a chronological age-related disease. As biological aging process is not absolutely determined by increasing age, whether alveolar bone loss is associated with increasing chronological age or biological aging remains unclear. Accurately distinguishing whether alveolar bone loss is chronological age-related or biological aging-related is critical for selecting appropriate clinical treatments. This study aimed to identify the relationship between alveolar bone loss and body aging. In total, 3 635 participants from the National Health and Nutrition Examination Survey and 71 living kidney transplant recipients from Gene Expression Omnibus Datasets were enrolled. Multivariate regression analysis, smooth curve fittings, and generalized additive models were used to explore the association among alveolar bone loss, age, serum α-Klotho level, renal function markers, as well as between preoperative creatinine and renal cortex-related α-Klotho gene expression level. Meanwhile, a 2-sample Mendelian randomization (MR) study was conducted to assess the causal relationship between α-Klotho and periodontal disease (4 376 individuals vs 361 194 individuals). As a biological aging-related indicator, the α-Klotho level was negatively correlated with impaired renal function and alveolar bone loss. Correspondingly, accompanied by decreasing renal function, it was manifested with a downregulated expression level of α-Klotho in the renal cortex and aggravated alveolar bone loss. The MR analysis further identified the negative association between higher genetically predicted α-Klotho concentrations with alveolar bone loss susceptibility using the IVW (odds ratio [OR] = 0.999, p = .005). However, an inversely U-shaped association was observed between chronological age and alveolar bone loss, which is especially stable in men (the optimal cutoff values were both 62 years old). For men above 62 years old, increasing age is converted to protective factor and is accompanied by alleviated alveolar bone loss. Alveolar bone loss that is directly associated with decreased renal function and α-Klotho level was related to biological aging rather than chronological age. The renal-alveolar bone axis could provide a new sight of clinical therapy in alveolar bone loss.
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Affiliation(s)
- Zifei Wang
- Key Laboratory of Oral Diseases Research of Anhui Province, College & Hospital of Stomatology, Anhui Medical University, Hefei, China
| | - Hao Xue
- Department of Stomatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yuqiang Sun
- Key Laboratory of Oral Diseases Research of Anhui Province, College & Hospital of Stomatology, Anhui Medical University, Hefei, China
| | - Qing Wang
- Key Laboratory of Oral Diseases Research of Anhui Province, College & Hospital of Stomatology, Anhui Medical University, Hefei, China
| | - Wansu Sun
- Department of Stomatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hengguo Zhang
- Key Laboratory of Oral Diseases Research of Anhui Province, College & Hospital of Stomatology, Anhui Medical University, Hefei, China
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Yamada H, Kuro-O M, Funazaki S, Hamamoto K, Hara K. Soluble αKlotho concentration in the inferior vena cava of patients with primary aldosteronism. Nefrologia 2024; 44:623-627. [PMID: 39547775 DOI: 10.1016/j.nefroe.2024.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 04/21/2024] [Indexed: 11/17/2024] Open
Abstract
INTRODUCTION Klotho, a key aging regulator, is predominantly expressed in the kidney. Various methods now enable the measurement of soluble αKlotho blood levels in humans. Limited studies have explored the renal origin of circulating αKlotho in humans. METHODS Soluble αKlotho in the inferior vena cava blood was measured using an enzyme-linked immunosorbent assay kit using blood samples from patients undergoing adrenal venous catheterization for close examination of primary aldosteronism. RESULTS The concentration at the suprarenal inferior vena cava (476±68.2) was significantly higher than that at the infrarenal inferior vena cava (434±74.8) (p=0.018), with a rate of change of 8.12 (2.3)%. CONCLUSIONS We demonstrate a step-up in αKlotho concentration from the infrarenal to suprarenal vena cava in humans, supporting the kidney's origin of soluble αKlotho in the bloodstream.
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Affiliation(s)
- Hodaka Yamada
- Department of Medicine, Division of Endocrinology and Metabolism, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama 330-8503, Japan.
| | - Makoto Kuro-O
- Division of Anti-aging Medicine, Center for Molecular Medicine, Jichi Medical University, 3311-1, Shimotsuke, Tochigi 329-0498, Japan
| | - Shunsuke Funazaki
- Department of Medicine, Division of Endocrinology and Metabolism, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama 330-8503, Japan
| | - Kohei Hamamoto
- Department of Radiology, School of Medicine, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama 330-8503, Japan
| | - Kazuo Hara
- Department of Medicine, Division of Endocrinology and Metabolism, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama 330-8503, Japan
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Wang X, Chang HC, Gu X, Han W, Mao S, Lu L, Jiang S, Ding H, Han S, Qu X, Bao Z. Renal lipid accumulation and aging linked to tubular cells injury via ANGPTL4. Mech Ageing Dev 2024; 219:111932. [PMID: 38580082 DOI: 10.1016/j.mad.2024.111932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 04/02/2024] [Indexed: 04/07/2024]
Abstract
Renal tubular epithelial cells are vulnerable to stress-induced damage, including excessive lipid accumulation and aging, with ANGPTL4 potentially playing a crucial bridging role between these factors. In this study, RNA-sequencing was used to identify a marked increase in ANGPTL4 expression in kidneys of diet-induced obese and aging mice. Overexpression and knockout of ANGPTL4 in renal tubular epithelial cells (HK-2) was used to investigate the underlying mechanism. Subsequently, ANGPTL4 expression in plasma and kidney tissues of normal young controls and elderly individuals was analyzed using ELISA and immunohistochemical techniques. RNA sequencing results showed that ANGPTL4 expression was significantly upregulated in the kidney tissue of diet-induced obesity and aging mice. In vitro experiments demonstrated that overexpression of ANGPTL4 in HK-2 cells led to increased lipid deposition and senescence. Conversely, the absence of ANGPTL4 appears to alleviate the impact of free fatty acids (FFA) on aging in HK-2 cells. Additionally, aging HK-2 cells exhibited elevated ANGPTL4 expression, and stress response markers associated with cell cycle arrest. Furthermore, our clinical evidence revealed dysregulation of ANGPTL4 expression in serum and kidney tissue samples obtained from elderly individuals compared to young subjects. Our study findings indicate a potential association between ANGPTL4 and age-related metabolic disorders, as well as injury to renal tubular epithelial cells. This suggests that targeting ANGPTL4 could be a viable strategy for the clinical treatment of renal aging.
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Affiliation(s)
- Xiaojun Wang
- Department of Gerontology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Hung-Chen Chang
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Department of Cardiology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Xuchao Gu
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Department of Traditional Chinese Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Wanlin Han
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Department of Cardiology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Shihang Mao
- Department of ENT Institute and Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, NHC Key Laboratory of Hearing Medicine Research, Fudan University, Shanghai, China
| | - Lili Lu
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Department of Traditional Chinese Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Shuai Jiang
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Department of Thoracic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Haiyong Ding
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Department of Urologic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China.
| | - Shisheng Han
- Department of Nephrology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Xinkai Qu
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Department of Cardiology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China.
| | - Zhijun Bao
- Department of Gerontology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China.
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Wang Y, Ran L, Lan Q, Liao W, Wang L, Wang Y, Xiong J, Li F, Yu W, Li Y, Huang Y, He T, Wang J, Zhao J, Yang K. Imbalanced lipid homeostasis caused by membrane αKlotho deficiency contributes to the acute kidney injury to chronic kidney disease transition. Kidney Int 2023; 104:956-974. [PMID: 37673285 DOI: 10.1016/j.kint.2023.08.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 07/28/2023] [Accepted: 08/11/2023] [Indexed: 09/08/2023]
Abstract
After acute kidney injury (AKI), renal tubular epithelial cells (RTECs) are pathologically characterized by intracellular lipid droplet (LD) accumulation, which are involved in RTEC injury and kidney fibrosis. However, its pathogenesis remains incompletely understood. The protein, αKlotho, primarily expressed in RTECs, is well known as an anti-aging hormone wielding versatile functions, and its membrane form predominantly acts as a co-receptor for fibroblast growth factor 23. Here, we discovered a connection between membrane αKlotho and intracellular LDs in RTECs. Fluorescent fatty acid (FA) pulse-chase assays showed that membrane αKlotho deficiency in RTECs, as seen in αKlotho homozygous mutated (kl/kl) mice or in mice with ischemia-reperfusion injury (IRI)-induced AKI, inhibited FA mobilization from LDs by impairing adipose triglyceride lipase (ATGL)-mediated lipolysis and lipophagy. This resulted in LD accumulation and FA underutilization. IRI-induced alterations were more striking in αKlotho deficiency. Mechanistically, membrane αKlotho deficiency promoted E3 ligase peroxin2 binding to ubiquitin-conjugating enzyme E2 D2, resulting in ubiquitin-mediated degradation of ATGL which is a common molecular basis for lipolysis and lipophagy. Overexpression of αKlotho rescued FA mobilization by preventing ATGL ubiquitination, thereby lessening LD accumulation and fibrosis after AKI. This suggests that membrane αKlotho is indispensable for the maintenance of lipid homeostasis in RTECs. Thus, our study identified αKlotho as a critical regulator of lipid turnover and homeostasis in AKI, providing a viable strategy for preventing tubular injury and the AKI-to-chronic kidney disease transition.
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Affiliation(s)
- Yue Wang
- Department of Nephrology, Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Li Ran
- Department of Nephrology, Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Qigang Lan
- Department of Nephrology, Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Weinian Liao
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Liting Wang
- Biomedical Analysis Center, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yaqin Wang
- Department of Nephrology, Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jiachuan Xiong
- Department of Nephrology, Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Fugang Li
- Department of Nephrology, Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Wenrui Yu
- Department of Nephrology, Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yan Li
- Department of Nephrology, Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yinghui Huang
- Department of Nephrology, Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Ting He
- Department of Nephrology, Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Junping Wang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jinghong Zhao
- Department of Nephrology, Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
| | - Ke Yang
- Department of Nephrology, Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
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9
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Egli-Spichtig D, Hamid AK, Arroyo EMP, Ketteler M, Wiecek A, Rosenkranz AR, Pasch A, Lorenz H, Hellmann B, Karus M, Ammer R, Rubio-Aliaga I, Wagner CA. Intact FGF23 predicts serum phosphate improvement after combined nicotinamide and phosphate binder treatment in hemodialysis patients. Clin Kidney J 2023; 16:1622-1633. [PMID: 37779856 PMCID: PMC10539220 DOI: 10.1093/ckj/sfad040] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Indexed: 10/03/2023] Open
Abstract
Background Hyperphosphatemia is associated with increased mortality and cardiovascular morbidity of end-stage kidney failure (ESKF) patients. Managing serum phosphate in ESKF patients is challenging and mostly based on limiting intestinal phosphate absorption with low phosphate diets and phosphate binders (PB). In a multi-centric, double-blinded, placebo-controlled study cohort of maintenance hemodialysis patients with hyperphosphatemia, we demonstrated the efficacy of nicotinamide modified release (NAMR) formulation treatment in addition to standard PB therapy in decreasing serum phosphate. Here we aimed to assess the relationship between phosphate, FGF23, inflammation and iron metabolism in this cohort. Methods We measured the plasma concentrations of intact fibroblast growth factor 23 (iFGF23) and selected proinflammatory cytokines at baseline and Week 12 after initiating treatment. Results We observed a strong correlation between iFGF23 and cFGF23 (C-terminal fragment plus iFGF23). We identified iFGF23 as a better predictor of changes in serum phosphate induced by NAMR and PB treatment compared with cFGF23. Recursive partitioning revealed at baseline and Week 12, that iFGF23 and cFGF23 together with T50 propensity were the most important predictors of serum phosphate, whereas intact parathyroid hormone (iPTH) played a minor role in this model. Furthermore, we found serum phosphate and iPTH as the best predictors of iFGF23 and cFGF23. Sex, age, body mass index, and markers of inflammation and iron metabolism had only a minor impact in predicting FGF23. Conclusion Lowering serum phosphate in ESKF patients may depend highly on iFGF23 which is correlated to cFGF23 levels. Serum phosphate was the most important predictor of plasma FGF23 in this ESKF cohort.
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Affiliation(s)
- Daniela Egli-Spichtig
- Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland, and National Center of Competence in Research NCCR Kidney.CH
| | - Ahmad Kamal Hamid
- Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland, and National Center of Competence in Research NCCR Kidney.CH
| | - Eva Maria Pastor Arroyo
- Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland, and National Center of Competence in Research NCCR Kidney.CH
| | - Markus Ketteler
- Robert Bosch Hospital, Department of General Internal Medicine and Nephrology, Stuttgart, Germany
| | - Andrzej Wiecek
- Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, Katowice, Poland
| | - Alexander R Rosenkranz
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Andreas Pasch
- Calciscon AG, 2503 Biel, Switzerland
- Department of Nephrology, Lindenhofspital, 3012 Bern, Switzerland
- Department of Physiology and Pathophysiology, Johannes Kepler University Linz, Linz, Austria
| | - Horst Lorenz
- Buero fuer Biometrie und Statistik, Neuberg, Germany
| | | | - Michael Karus
- MEDICE Arzneimittel Pütter GmbH & Co KG, Iserlohn, Germany
| | - Richard Ammer
- MEDICE Arzneimittel Pütter GmbH & Co KG, Iserlohn, Germany
- Department of Medicine D, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital of Münster, Münster, Germany
| | - Isabel Rubio-Aliaga
- Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland, and National Center of Competence in Research NCCR Kidney.CH
| | - Carsten A Wagner
- Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland, and National Center of Competence in Research NCCR Kidney.CH
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10
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Evenepoel P, Stenvinkel P, Shanahan C, Pacifici R. Inflammation and gut dysbiosis as drivers of CKD-MBD. Nat Rev Nephrol 2023; 19:646-657. [PMID: 37488276 DOI: 10.1038/s41581-023-00736-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/19/2023] [Indexed: 07/26/2023]
Abstract
Two decades ago, Kidney Disease: Improving Global Outcomes coined the term chronic kidney disease-mineral and bone disorder (CKD-MBD) to describe the syndrome of biochemical, bone and extra-skeletal calcification abnormalities that occur in patients with CKD. CKD-MBD is a prevalent complication and contributes to the excessively high burden of fractures and cardiovascular disease, loss of quality of life and premature mortality in patients with CKD. Thus far, therapy has focused primarily on phosphate retention, abnormal vitamin D metabolism and parathyroid hormone disturbances, but these strategies have largely proved unsuccessful, thus calling for paradigm-shifting concepts and innovative therapeutic approaches. Interorgan crosstalk is increasingly acknowledged to have an important role in health and disease. Accordingly, mounting evidence suggests a role for both the immune system and the gut microbiome in bone and vascular biology. Gut dysbiosis, compromised gut epithelial barrier and immune cell dysfunction are prominent features of the uraemic milieu. These alterations might contribute to the inflammatory state observed in CKD and could have a central role in the pathogenesis of CKD-MBD. The emerging fields of osteoimmunology and osteomicrobiology add another level of complexity to the pathogenesis of CKD-MBD, but also create novel therapeutic opportunities.
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Affiliation(s)
- Pieter Evenepoel
- Laboratory of Nephrology, Department of Microbiology, Immunology, and Transplantation, KU Leuven, Herestraat, Leuven, Belgium.
| | - Peter Stenvinkel
- Department of Renal Medicine M99, Karolinska University Hospital, Stockholm, Sweden
| | - Catherine Shanahan
- British Heart Foundation Centre of Excellence, School of Cardiovascular and Metabolic Medicine and Sciences, King's College London, London, UK
| | - Roberto Pacifici
- Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory Microbiome Research Center, and Immunology and Molecular Pathogenesis Program, Emory University, Atlanta, GA, USA
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11
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Torregrosa JV, Bover J, Rodríguez Portillo M, González Parra E, Dolores Arenas M, Caravaca F, González Casaus ML, Martín-Malo A, Navarro-González JF, Lorenzo V, Molina P, Rodríguez M, Cannata Andia J. Recommendations of the Spanish Society of Nephrology for the management of mineral and bone metabolism disorders in patients with chronic kidney disease: 2021 (SEN-MM). Nefrologia 2023; 43 Suppl 1:1-36. [PMID: 37202281 DOI: 10.1016/j.nefroe.2023.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 03/26/2022] [Indexed: 05/20/2023] Open
Abstract
As in 2011, when the Spanish Society of Nephrology (SEN) published the Spanish adaptation to the Kidney Disease: Improving Global Outcomes (KDIGO) universal Guideline on Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD), this document contains an update and an adaptation of the 2017 KDIGO guidelines to our setting. In this field, as in many other areas of nephrology, it has been impossible to irrefutably answer many questions, which remain pending. However, there is no doubt that the close relationship between the CKD-MBD/cardiovascular disease/morbidity and mortality complex and new randomised clinical trials in some areas and the development of new drugs have yielded significant advances in this field and created the need for this update. We would therefore highlight the slight divergences that we propose in the ideal objectives for biochemical abnormalities in the CKD-MBD complex compared to the KDIGO suggestions (for example, in relation to parathyroid hormone or phosphate), the role of native vitamin D and analogues in the control of secondary hyperparathyroidism and the contribution of new phosphate binders and calcimimetics. Attention should also be drawn to the adoption of important new developments in the diagnosis of bone abnormalities in patients with kidney disease and to the need to be more proactive in treating them. In any event, the current speed at which innovations are taking place, while perhaps slower than we might like, globally drives the need for more frequent updates (for example, through Nefrología al día).
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Affiliation(s)
| | - Jordi Bover
- Hospital Germans Trias i Pujol, Badalona, Spain
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12
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Donate-Correa J, Martín-Núñez E, Martin-Olivera A, Mora-Fernández C, Tagua VG, Ferri CM, López-Castillo Á, Delgado-Molinos A, López-Tarruella VC, Arévalo-Gómez MA, Pérez-Delgado N, González-Luis A, Navarro-González JF. Klotho inversely relates with carotid intima- media thickness in atherosclerotic patients with normal renal function (eGFR ≥60 mL/min/1.73m 2): a proof-of-concept study. Front Endocrinol (Lausanne) 2023; 14:1146012. [PMID: 37274332 PMCID: PMC10235765 DOI: 10.3389/fendo.2023.1146012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 04/26/2023] [Indexed: 06/06/2023] Open
Abstract
INTRODUCTION Klotho protein is predominantly expressed in the kidneys and has also been detected in vascular tissue and peripheral blood circulating cells to a lesser extent. Carotid artery intima-media thickness (CIMT) burden, a marker of subclinical atherosclerosis, has been associated with reductions in circulating Klotho levels in chronic kidney disease patients, who show reduced levels of this protein at all stages of the disease. However, the contribution of serum Klotho and its expression levels in peripheral blood circulating cells and in the carotid artery wall on the CIMT in the absence of kidney impairment has not yet been evaluated. METHODS We conducted a single-center study in 35 atherosclerotic patients with preserved kidney function (eGFR≥60 mL/min/1.73m2) subjected to elective carotid surgery. Serum levels of Klotho and cytokines TNFa, IL6 and IL10 were determined by ELISA and transcripts encoding for Klotho (KL), TNF, IL6 and IL10 from vascular segments were measured by qRT-PCR. Klotho protein expression in the intima-media and adventitia areas was analyzed using immunohistochemistry. RESULTS APatients with higher values of CIMT showed reduced Klotho levels in serum (430.8 [357.7-592.9] vs. 667.8 [632.5-712.9] pg/mL; p<0.001), mRNA expression in blood circulating cells and carotid artery wall (2.92 [2.06-4.8] vs. 3.69 [2.42-7.13] log.a.u., p=0.015; 0.41 [0.16-0.59] vs. 0.79 [0.37-1.4] log.a.u., p=0.013, respectively) and immunoreactivity in the intimal-medial area of the carotids (4.23 [4.15-4.27] vs. 4.49 [4.28-4.63] log µm2 p=0.008). CIMT was inversely related with Klotho levels in serum (r= -0.717, p<0.001), blood mRNA expression (r=-0.426, p=0.011), and with carotid artery mRNA and immunoreactivity levels (r= -0.45, p=0.07; r= -0.455, p= 0.006, respectively). Multivariate analysis showed that serum Klotho, together with the gene expression levels of tumor necrosis factor TNFa in blood circulating cells, were independent determinants of CIMT values (adjusted R2 = 0.593, p<0.001). DISCUSSION The results of this study in subjects with eGFR≥60mL/min/1.73m2 show that patients with carotid artery atherosclerosis and higher values of CIMT present reduced soluble Klotho levels, as well as decreased KL mRNA expression in peripheral blood circulating cells and Klotho protein levels in the intima-media of the carotid artery wall.
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Affiliation(s)
- Javier Donate-Correa
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria (HUNSC), Santa Cruz de Tenerife, Spain
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, Santander, Spain
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, Santa Cruz de Tenerife, Spain
- RICORS2040 (Red de Investigación Renal-RD21/0005/0013), Instituto de Salud Carlos III, Madrid, Spain
| | - Ernesto Martín-Núñez
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria (HUNSC), Santa Cruz de Tenerife, Spain
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, Santander, Spain
| | - Alberto Martin-Olivera
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria (HUNSC), Santa Cruz de Tenerife, Spain
| | - Carmen Mora-Fernández
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria (HUNSC), Santa Cruz de Tenerife, Spain
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, Santander, Spain
- RICORS2040 (Red de Investigación Renal-RD21/0005/0013), Instituto de Salud Carlos III, Madrid, Spain
| | - Víctor G. Tagua
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria (HUNSC), Santa Cruz de Tenerife, Spain
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, Santa Cruz de Tenerife, Spain
- Área de Medicina Preventiva y Salud Pública, Universidad de La Laguna, San Cristóbal de La Laguna, Spain
| | - Carla M. Ferri
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria (HUNSC), Santa Cruz de Tenerife, Spain
- Escuela de Doctorado y Estudios de Posgrado, Universidad de La Laguna, San Cristóbal de La Laguna, Spain
| | | | | | | | | | | | - Ainhoa González-Luis
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria (HUNSC), Santa Cruz de Tenerife, Spain
- Escuela de Doctorado y Estudios de Posgrado, Universidad de La Laguna, San Cristóbal de La Laguna, Spain
| | - Juan F. Navarro-González
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria (HUNSC), Santa Cruz de Tenerife, Spain
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, Santander, Spain
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, Santa Cruz de Tenerife, Spain
- RICORS2040 (Red de Investigación Renal-RD21/0005/0013), Instituto de Salud Carlos III, Madrid, Spain
- Servicio de Nefrología, HUNSC, Santa Cruz de Tenerife, Spain
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13
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Neves JS, Buysschaert M, Bergman M. Editorial: Prediabetes: new insights on the diagnosis, risk stratification, comorbidites, cardiovascular disease, microvascular complications, and treatment. Front Endocrinol (Lausanne) 2023; 14:1214479. [PMID: 37251678 PMCID: PMC10210134 DOI: 10.3389/fendo.2023.1214479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Accepted: 05/04/2023] [Indexed: 05/31/2023] Open
Affiliation(s)
- João Sérgio Neves
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal
- Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Martin Buysschaert
- Department of Endocrinology and Diabetology, Université Catholique de Louvain, University Clinic Saint-Luc, Brussels, Belgium
| | - Michael Bergman
- Division of Endocrinology, Diabetes and Metabolism, New York University Grossman School of Medicine, New York, NY, United States
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14
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Thi Nguyen N, Thi Nguyen T, Nguyen HT, Lee JM, Kim MJ, Qi XF, Cha SK, Lee IK, Park KS. Inhibition of mitochondrial phosphate carrier prevents high phosphate-induced superoxide generation and vascular calcification. Exp Mol Med 2023; 55:532-540. [PMID: 36854772 PMCID: PMC10073177 DOI: 10.1038/s12276-023-00950-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 12/07/2022] [Accepted: 12/15/2022] [Indexed: 03/02/2023] Open
Abstract
Vascular calcification is a serious complication of hyperphosphatemia that causes cardiovascular morbidity and mortality. Previous studies have reported that plasmalemmal phosphate (Pi) transporters, such as PiT-1/2, mediate depolarization, Ca2+ influx, oxidative stress, and calcific changes in vascular smooth muscle cells (VSMCs). However, the pathogenic mechanism of mitochondrial Pi uptake in vascular calcification associated with hyperphosphatemia has not been elucidated. We demonstrated that the phosphate carrier (PiC) is the dominant mitochondrial Pi transporter responsible for high Pi-induced superoxide generation, osteogenic gene upregulation, and calcific changes in primary VSMCs isolated from rat aortas. Notably, acute incubation with high Pi markedly increased the protein abundance of PiC via ERK1/2- and mTOR-dependent translational upregulation. Genetic suppression of PiC prevented Pi-induced ERK1/2 activation, superoxide production, osteogenic differentiation, and vascular calcification of VSMCs in vitro and aortic rings ex vivo. Pharmacological inhibition of mitochondrial Pi transport using butyl malonate (BMA) or mersalyl abolished all pathologic changes involved in high Pi-induced vascular calcification. BMA or mersalyl also effectively prevented osteogenic gene upregulation and calcification of aortas from 5/6 subtotal nephrectomized mice fed a high-Pi diet. Our results suggest that mitochondrial Pi uptake via PiC is a critical molecular mechanism mediating mitochondrial superoxide generation and pathogenic calcific changes, which could be a novel therapeutic target for treating vascular calcification associated with hyperphosphatemia.
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Affiliation(s)
- Nhung Thi Nguyen
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea.,Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Medical Doctor Program, College of Health Sciences, VinUniversity, Hanoi, Vietnam
| | - Tuyet Thi Nguyen
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea. .,Internal Medicine Residency Program, VinUniversity, Hanoi, Vietnam.
| | - Ha Thu Nguyen
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea.,Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Ji-Min Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Korea
| | - Min-Ji Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Korea
| | - Xu-Feng Qi
- Key Laboratory of Regenerative Medicine, Ministry of Education, Department of Developmental and Regenerative Biology, Jinan University, Guangzhou, China
| | - Seung-Kuy Cha
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea.,Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - In-Kyu Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Korea.
| | - Kyu-Sang Park
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea. .,Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.
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15
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Mok Y, Wang F, Ballew SH, Menez S, Butler KR, Wagenknecht L, Sedaghat S, Lutsey PL, Coresh J, Blaha MJ, Matsushita K. Kidney function, bone-mineral metabolism markers, and calcification of coronary arteries, aorta, and cardiac valves in older adults. Atherosclerosis 2023; 368:35-43. [PMID: 36754659 PMCID: PMC9992265 DOI: 10.1016/j.atherosclerosis.2023.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 01/10/2023] [Indexed: 01/15/2023]
Abstract
BACKGROUND AND AIMS The contribution of kidney dysfunction, especially at mild-to-moderate stages, and bone-mineral metabolism (BMM) markers to vascular calcification remains controversial or unclear. We comprehensively evaluated the association of kidney and BMM markers with coronary artery calcification (CAC) and extra-coronary calcification (ECC). METHODS In 1931 ARIC participants (age 73-95 years) without coronary heart disease at visit 7 (2018-19), we investigated the associations of estimated glomerular filtration rate (eGFR) (with creatinine, cystatin C, and both) and five serum BMM markers (calcium, fibroblast growth factor 23, magnesium, parathyroid hormone, and phosphorus) with high CAC and ECC (sex-race specific ≥75th vs. <75th percentile Agatston score) or any vs. zero CAC and ECC using multivariable logistic regression. For eGFR and BMM markers, we took their weighted cumulative averages from visit 1 (1987-89) to visit 5 (2011-13). RESULTS Lower eGFR, regardless of equations used, was not robustly associated with high CAC or ECC. Among BMM markers, only higher phosphorus levels, even within the normal range, showed robust associations with high CAC (only when modeled continuously) and ECC, independently of kidney function (e.g., odds ratio 1.94 [95%CI 1.38-2.73] for high aortic valve calcification, in the highest vs. lowest quartile). Results were generally consistent when analyzing any CAC or ECC, although cystatin C-based eGFR <60 mL/min/1.73 m2 became significantly associated with mitral valve calcification (odds ratio 1.69 [1.10-2.60]). CONCLUSIONS Among kidney and BMM measures tested, only serum phosphorus demonstrated robust associations with both CAC and ECC, supporting a key role of phosphorus in the pathophysiology of vascular calcification.
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Affiliation(s)
- Yejin Mok
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Frances Wang
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Shoshana H Ballew
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Steve Menez
- Division of Nephrology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Kenneth R Butler
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA
| | - Lynne Wagenknecht
- Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Sanaz Sedaghat
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA
| | - Pamela L Lutsey
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA
| | - Josef Coresh
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Michael J Blaha
- Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Kunihiro Matsushita
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
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16
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Calatroni M, Moroni G, Ponticelli C. Renal replacement therapy in sarcoidosis. Front Med (Lausanne) 2023; 9:990252. [PMID: 36698835 PMCID: PMC9870065 DOI: 10.3389/fmed.2022.990252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 12/16/2022] [Indexed: 01/11/2023] Open
Abstract
Sarcoidosis is a systemic inflammatory disease of unknown etiology. Kidney involvement in sarcoidosis may be present in up 25-30% of cases. An early diagnosis and prompt treatment with corticosteroids can improve the prognosis but rarely renal sarcoidosis can lead to kidney failure needing renal replacement therapy (RRT). Acute kidney injury (AKI) in sarcoidosis may be caused by granulomatous interstitial nephritis (GIN) or hypercalcemia. These disorders are usually clinically silent and may lead end stage renal disease (ESKD) if not diagnosed or detected too late. In patients with ESKD, dialysis and renal transplantation can offer results comparable to those observed in patients with other causes of kidney failure. Based on a review of literature, we present an overview of RRT in patients with AKI or chronic kidney disease (CKD) caused by sarcoidosis.
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Affiliation(s)
- Marta Calatroni
- Department of Biomedical Sciences, Humanitas University, Milan, Italy,Nephrology and Dialysis Division, IRCCS Humanitas Research Hospital, Milan, Italy,*Correspondence: Marta Calatroni,
| | - Gabriella Moroni
- Department of Biomedical Sciences, Humanitas University, Milan, Italy,Nephrology and Dialysis Division, IRCCS Humanitas Research Hospital, Milan, Italy
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17
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Association of combined fractional excretion of phosphate and FGF23 with heart failure and cardiovascular events in moderate and advanced renal disease. J Nephrol 2023; 36:55-67. [PMID: 35678953 DOI: 10.1007/s40620-022-01358-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 05/15/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND High levels of FGF23 associate with adverse events in CKD. The urinary fractional excretion of phosphate (FePi) might modify this association, although data are limited in moderate and advanced CKD. We investigated the association of combined FePi and serum FGF23 with incident heart failure, cardiovascular events and mortality in patients with CKD stages 2-4. METHODS Patients from the Chronic Renal Insufficiency Cohort were divided into four groups according to the median of FePi and FGF23: low-FePi/low-FGF23, reference group; high-FePi/low-FGF23; low-FePi/high-FGF23; high-FePi/high-FGF23. Primary outcomes were: the composite of cardiovascular death or hospitalization for heart failure; cardiovascular death; hospitalization for heart failure; and death from any cause. Survival analysis and adjusted regression analyses were performed. RESULTS We analyzed 3684 patients with a mean age of 58 ± 11 years of whom 45% were male. Mean eGFR was 44 ± 15 ml/min/1.73 m2. The median time of follow-up was 12 (IQR 7-13) years. The risk of the composite of cardiovascular death or hospitalization for heart failure was increased in the low-FePi/high-FGF23 group (HR 1.35; 95%CI 1.09-1.67) and in the high-FePi/high-FGF23 group (HR 1.50; 95%CI 1.20-1.86), compared to the low-FePi/low-FGF23 group. Cardiovascular death and hospitalization for heart failure were also increased in both groups with high FGF23. Death from any cause was increased in the low-FePi/high-FGF23 group (HR 1.56 (95%CI 1.30-1.89) and in the high-FePi/high-FGF23 (HR 1.57 (95%CI 1.29-1.90)). CONCLUSIONS High FGF23 was associated with heart failure and cardiovascular death in patients with low FePi and high FePi with moderate to advanced CKD. This contrasts with reports in mild CKD.
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18
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Kritmetapak K, Kumar R. Phosphatonins: From Discovery to Therapeutics. Endocr Pract 2023; 29:69-79. [PMID: 36210014 DOI: 10.1016/j.eprac.2022.09.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 09/22/2022] [Accepted: 09/23/2022] [Indexed: 01/11/2023]
Abstract
OBJECTIVE Phosphate is crucial for cell signaling, energy metabolism, nucleotide synthesis, and bone mineralization. The gut-bone-parathyroid-kidney axis is influenced by parathyroid hormone, 1,25-dihydroxyvitamin D, and phosphatonins, especially fibroblast growth factor 23 (FGF23). These hormones facilitate maintenance of phosphate homeostasis. This review summarizes current knowledge regarding the phosphate homeostasis, phosphatonin pathophysiology, and clinical implications of FGF23-related hypophosphatemic disorders, with specific focus on burosumab treatment. METHOD A focused literature search of PubMed was conducted. RESULTS Phosphatonins including FGF23, secreted frizzled-related protein 4, matrix extracellular phosphoglycoprotein, and fibroblast growth factor 7 play a pathogenic role in several hypophosphatemic disorders. Excess FGF23 inhibits sodium-dependent phosphate cotransporters (NaPi-2a and NaPi-2c), resulting in hyperphosphaturia and hypophosphatemia. Additionally, FGF23 suppresses 1,25-dihydroxyvitamin D synthesis in the proximal renal tubule, and thus, it indirectly inhibits intestinal phosphate absorption. Disorders of FGF23-related hypophosphatemia include X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, fibrous dysplasia/McCune-Albright syndrome, and tumor-induced osteomalacia (TIO). Complications of conventional therapy with oral phosphate and vitamin D analogs comprise gastrointestinal distress, hypercalcemia, nephrocalcinosis, and secondary/tertiary hyperparathyroidism. In both children and adults with XLH and TIO, the anti-FGF23 antibody burosumab exhibits a favorable safety profile and is associated with healing of rickets in affected children and improvement of osteomalacia in both children and adults. CONCLUSION The treatment paradigm for XLH and TIO is changing based on data from recent clinical trials. Research suggest that burosumab is effective and safe for pediatric and adult patients with XLH or TIO.
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Affiliation(s)
| | - Rajiv Kumar
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.
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19
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Jena S, Sarangi P, Das UK, Lamare AA, Rattan R. Serum α- Klotho Protein Can Be an Independent Predictive Marker of Oxidative Stress (OS) and Declining Glomerular Function Rate in Chronic Kidney Disease (CKD) Patients. Cureus 2022; 14:e25759. [PMID: 35812534 PMCID: PMC9268485 DOI: 10.7759/cureus.25759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/08/2022] [Indexed: 12/03/2022] Open
Abstract
Introduction Chronic kidney disease (CKD) has been recognized as a global health problem. Progression of CKD to advanced stages is associated with a significant increase in the generation of reactive oxygen species (ROS). An antiaging protein, α-Klotho, is found expressed in the distal convoluted tubules of the kidney where, predominantly, it works to increase calcium absorption and potassium excretion in distal tubule via N-linked glycans. The association of serum α-Klotho with oxidative stress, inflammation, and fibrosis, as seen in CKD, highlights its importance for studying disease prognosis with declining glomerular function rate (GFR). Material and methods This was a case-control study consisting of 90 subjects. Fifty diagnosed cases of CKD attending the department of nephrology, SCB Medical College, Cuttack, Odisha, were included, and 40 age and sex-matched healthy volunteers were taken as control. Serum α-Klotho levels were measured using enzyme-linked immunosorbent assay kits. Oxidative stress by estimating the total oxidant load by ferrous oxidation-xylenol orange version 2 (FOX2) method and the total antioxidant capacity of serum by the ferric reducing ability of plasma (FRAP) method. Estimation of the estimated glomerular filtration rate (eGFR) was done using the Cockcroft and Gault equation. Results Serum α-Klotho (ng/ml) was found to be 2.59±0.98 in cases as compared to 0.24±0.09 in controls (p< 0.01). The serum total oxidant load (ng/ml) was 1.96±1.01 and 0.05±0.02 in cases and controls, respectively. Serum total antioxidant capacity (µM) was measured as 281.80±78.0 in cases and 862.82±51.86 in controls. (p< 0.01). Serum Klotho has a negative correlation with eGFR in CKD patients (r = -0.065; p = 0.648). Conclusion The serum α-Klotho level was significantly higher in CKD patients than in healthy volunteers. Both serum α-Klotho and oxidative stress were negatively correlated with eGFR in CKD patients. Serum α-Klotho can be a suitable biomarker in CKD patients with declining GFR.
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20
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αKlotho decreases after reduced weight-bearing from both spaceflight and hindlimb unloading. NPJ Microgravity 2022; 8:18. [PMID: 35654945 PMCID: PMC9163032 DOI: 10.1038/s41526-022-00203-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 05/13/2022] [Indexed: 11/16/2022] Open
Abstract
Alpha(α)Klotho, a soluble transmembrane protein, facilitates calcium-phosphorus homeostasis through feedback between bone and kidney and is a potential systemic biomarker for bone-kidney health during spaceflight. We determined if: (1) plasma αKlotho was reduced after both spaceflight aboard the ISS and hindlimb unloading (HU); and (2) deficiency could be reversed with exercise. Both spaceflight and HU lowered circulating plasma αKlotho: plasma αKlotho recovered with exercise after HU.
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21
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Gupta M, Orozco G, Rao M, Gedaly R, Malluche HH, Neyra JA. The Role of Alterations in Alpha-Klotho and FGF-23 in Kidney Transplantation and Kidney Donation. Front Med (Lausanne) 2022; 9:803016. [PMID: 35602513 PMCID: PMC9121872 DOI: 10.3389/fmed.2022.803016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 02/03/2022] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular disease and mineral bone disorders are major contributors to morbidity and mortality among patients with chronic kidney disease and often persist after renal transplantation. Ongoing hormonal imbalances after kidney transplant (KT) are associated with loss of graft function and poor outcomes. Fibroblast growth factor 23 (FGF-23) and its co-receptor, α-Klotho, are key factors in the underlying mechanisms that integrate accelerated atherosclerosis, vascular calcification, mineral disorders, and osteodystrophy. On the other hand, kidney donation is also associated with endocrine and metabolic adaptations that include transient increases in circulating FGF-23 and decreases in α-Klotho levels. However, the long-term impact of these alterations and their clinical relevance have not yet been determined. This manuscript aims to review and summarize current data on the role of FGF-23 and α-Klotho in the endocrine response to KT and living kidney donation, and importantly, underscore specific areas of research that may enhance diagnostics and therapeutics in the growing population of KT recipients and kidney donors.
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Affiliation(s)
- Meera Gupta
- Department of Surgery - Transplant Division, University of Kentucky, College of Medicine, Lexington, KY, United States
- Department of Surgery, University of Kentucky, Lexington, KY, United States
- *Correspondence: Meera Gupta
| | - Gabriel Orozco
- Department of Surgery - Transplant Division, University of Kentucky, College of Medicine, Lexington, KY, United States
- Department of Surgery, University of Kentucky, Lexington, KY, United States
| | - Madhumati Rao
- Department of Internal Medicine - Nephrology, Bone and Mineral Metabolism Division, University of Kentucky, College of Medicine, Lexington, KY, United States
| | - Roberto Gedaly
- Department of Surgery - Transplant Division, University of Kentucky, College of Medicine, Lexington, KY, United States
- Department of Surgery, University of Kentucky, Lexington, KY, United States
| | - Hartmut H. Malluche
- Department of Internal Medicine - Nephrology, Bone and Mineral Metabolism Division, University of Kentucky, College of Medicine, Lexington, KY, United States
| | - Javier A. Neyra
- Department of Internal Medicine - Nephrology, Bone and Mineral Metabolism Division, University of Kentucky, College of Medicine, Lexington, KY, United States
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Javier A. Neyra
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22
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Urine-Derived Stem Cell-Secreted Klotho Plays a Crucial Role in the HK-2 Fibrosis Model by Inhibiting the TGF-β Signaling Pathway. Int J Mol Sci 2022; 23:ijms23095012. [PMID: 35563402 PMCID: PMC9105028 DOI: 10.3390/ijms23095012] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 04/28/2022] [Accepted: 04/28/2022] [Indexed: 02/01/2023] Open
Abstract
Renal fibrosis is an irreversible and progressive process that causes severe dysfunction in chronic kidney disease (CKD). The progression of CKD stages is highly associated with a gradual reduction in serum Klotho levels. We focused on Klotho protein as a key therapeutic factor against CKD. Urine-derived stem cells (UDSCs) have been identified as a novel stem cell source for kidney regeneration and CKD treatment because of their kidney tissue-specific origin. However, the relationship between UDSCs and Klotho in the kidneys is not yet known. In this study, we discovered that UDSCs were stem cells that expressed Klotho protein more strongly than other mesenchymal stem cells (MSCs). UDSCs also suppressed fibrosis by inhibiting transforming growth factor (TGF)-β in HK-2 human renal proximal tubule cells in an in vitro model. Klotho siRNA silencing reduced the TGF-inhibiting ability of UDSCs. Here, we suggest an alternative cell source that can overcome the limitations of MSCs through the synergetic effect of the origin specificity of UDSCs and the anti-fibrotic effect of Klotho.
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23
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Sasaki S, Shiozaki Y, Hanazaki A, Koike M, Tanifuji K, Uga M, Kawahara K, Kaneko I, Kawamoto Y, Wiriyasermkul P, Hasegawa T, Amizuka N, Miyamoto KI, Nagamori S, Kanai Y, Segawa H. Tmem174, a regulator of phosphate transporter prevents hyperphosphatemia. Sci Rep 2022; 12:6353. [PMID: 35428804 PMCID: PMC9012787 DOI: 10.1038/s41598-022-10409-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 04/05/2022] [Indexed: 11/23/2022] Open
Abstract
Renal type II sodium-dependent inorganic phosphate (Pi) transporters NaPi2a and NaPi2c cooperate with other organs to strictly regulate the plasma Pi concentration. A high Pi load induces expression and secretion of the phosphaturic hormones parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) that enhance urinary Pi excretion and prevent the onset of hyperphosphatemia. How FGF23 secretion from bone is increased by a high Pi load and the setpoint of the plasma Pi concentration, however, are unclear. Here, we investigated the role of Transmembrane protein 174 (Tmem174) and observed evidence for gene co-expression networks in NaPi2a and NaPi2c function. Tmem174 is localized in the renal proximal tubules and interacts with NaPi2a, but not NaPi2c. In Tmem174-knockout (KO) mice, the serum FGF23 concentration was markedly increased but increased Pi excretion and hypophosphatemia were not observed. In addition, Tmem174-KO mice exhibit reduced NaPi2a responsiveness to FGF23 and PTH administration. Furthermore, a dietary Pi load causes marked hyperphosphatemia and abnormal NaPi2a regulation in Tmem174-KO mice. Thus, Tmem174 is thought to be associated with FGF23 induction in bones and the regulation of NaPi2a to prevent an increase in the plasma Pi concentration due to a high Pi load and kidney injury.
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Affiliation(s)
- Sumire Sasaki
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Yuji Shiozaki
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Ai Hanazaki
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Megumi Koike
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Kazuya Tanifuji
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Minori Uga
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Kota Kawahara
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Ichiro Kaneko
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Yasuharu Kawamoto
- Department of Bio-System Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Pattama Wiriyasermkul
- Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Tomoka Hasegawa
- Developmental Biology of Hard Tissue, Faculty of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Norio Amizuka
- Developmental Biology of Hard Tissue, Faculty of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Ken-Ichi Miyamoto
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.,Graduate School of Agriculture, Ryukoku University, Ohtsu, Japan
| | - Shushi Nagamori
- Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan.
| | - Yoshikatsu Kanai
- Department of Bio-System Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan.
| | - Hiroko Segawa
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
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24
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Yamada S, Tsuruya K, Kitazono T, Nakano T. Emerging cross-talks between chronic kidney disease-mineral and bone disorder (CKD-MBD) and malnutrition-inflammation complex syndrome (MICS) in patients receiving dialysis. Clin Exp Nephrol 2022; 26:613-629. [PMID: 35353283 PMCID: PMC9203392 DOI: 10.1007/s10157-022-02216-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 03/22/2022] [Indexed: 12/14/2022]
Abstract
Chronic kidney disease–mineral and bone disorder (CKD–MBD) is a systemic disorder that affects multiple organs and systems and increases the risk of morbidity and mortality in patients with CKD, especially those receiving dialysis therapy. CKD–MBD is highly prevalent in CKD patients, and its treatment is gaining attention from healthcare providers who manage these patients. Additional important pathologies often observed in CKD patients are chronic inflammation and malnutrition/protein-energy wasting (PEW). These two pathologies coexist to form a vicious cycle that accelerates the progression of various other pathologies in CKD patients. This concept is integrated into the term “malnutrition–inflammation–atherosclerosis syndrome” or “malnutrition–inflammation complex syndrome (MICS)”. Recent basic and clinical studies have shown that CKD–MBD directly induces inflammation as well as malnutrition/PEW. Indeed, higher circulating levels of inorganic phosphate, fibroblast growth factor 23, parathyroid hormone, and calciprotein particles, as markers for critical components and effectors of CKD–MBD, were shown to directly induce inflammatory responses, thereby leading to malnutrition/PEW, cardiovascular diseases, and clinically relevant complications. In this short review, we discuss the close interplay between CKD–MBD and MICS and emphasize the significance of simultaneous control of these two seemingly distinct pathologies in patients with CKD, especially those receiving dialysis therapy, for better management of the CKD/hemodialysis population.
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Affiliation(s)
- Shunsuke Yamada
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 8128582, Japan.
| | | | - Takanari Kitazono
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 8128582, Japan
| | - Toshiaki Nakano
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 8128582, Japan
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25
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Irsik DL, Bollag WB, Isales CM. Renal Contributions to Age-Related Changes in Mineral Metabolism. JBMR Plus 2021; 5:e10517. [PMID: 34693188 PMCID: PMC8520061 DOI: 10.1002/jbm4.10517] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 04/28/2021] [Accepted: 05/09/2021] [Indexed: 11/10/2022] Open
Abstract
Aging results in a general decline in function in most systems. This is particularly true with respect to the skeleton and renal systems, impacting mineral homeostasis. Calcium and phosphate regulation requires tight coordination among the intestine, bone, parathyroid gland, and kidney. The role of the intestine is to absorb calcium and phosphate from the diet. The bone stores or releases calcium and phosphate depending on the body's needs. In response to low plasma ionized calcium concentration, the parathyroid gland produces parathyroid hormone, which modulates bone turnover. The kidney reabsorbs or excretes the minerals and serves as the final regulator of plasma concentration. Many hormones are involved in this process in addition to parathyroid hormone, including fibroblast growth factor 23 produced by the bone and calcitriol synthesized by the kidney. Sclerostin, calcitonin, osteoprotegerin, and receptor activator of nuclear factor‐κB ligand also contribute to tissue‐specific regulation. Changes in the function of organs due to aging or disease can perturb this balance. During aging, the intestine cannot absorb calcium efficiently due to decreased expression of key proteins. In the bone, the balance between bone formation and bone resorption tends toward the latter in older individuals. The kidney may not filter blood as efficiently in the later decades of life, and the expression of certain proteins necessary for mineral homeostasis declines with age. These changes often lead to dysregulation of organismal mineral homeostasis. This review will focus on how mineral homeostasis is impacted by aging with a particular emphasis on the kidney's role in this process. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Debra L Irsik
- Charlie Norwood VA Medical Center Augusta GA USA.,Department of Neuroscience and Regenerative Medicine Augusta University Augusta GA USA
| | - Wendy B Bollag
- Charlie Norwood VA Medical Center Augusta GA USA.,Department of Physiology Augusta University Augusta GA USA
| | - Carlos M Isales
- Department of Neuroscience and Regenerative Medicine Augusta University Augusta GA USA.,Division of Endocrinology, Department of Medicine Augusta University Augusta GA USA
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26
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Huang S, Wang W, Cheng Y, Lin J, Wang M. Clinicopathological and Prognostic Significance of Klotho and Estrogen Receptors Expression in Human Hepatocellular Carcinoma. THE TURKISH JOURNAL OF GASTROENTEROLOGY : THE OFFICIAL JOURNAL OF TURKISH SOCIETY OF GASTROENTEROLOGY 2021; 32:828-836. [PMID: 34787087 PMCID: PMC8975321 DOI: 10.5152/tjg.2021.19986] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 09/21/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is male-predominant cancer, but the underlying mechanism remains unclear. This study aimed to investigate the expression of the age-suppressing gene klotho and estrogen receptors (ERs) in HCC patients and analyze their association with clinicopathological variables and their effects on prognosis. METHODS The expression patterns of klotho, ERα, and ERβ were determined by tissue microarray and immunohistochemical technique, and their correlations with clinicopathological characteristics were investigated using univariate and multivariate analysis. RESULTS Klotho expression was significantly lower in HCC than in the adjacent noncancerous tissues (52.7% (49/93) vs. 90.8% (79/87), P = .000), and its protein level in HCC tissue was negatively correlated with clinical staging, histological grade, and stage of the primary tumor (T) (P < .05). Whereas the expression of nuclear ERα and ERβ was higher in HCC than their corresponding non-neoplastic tissues (55.9% (52/93) vs. 35.6% (31/87), P = .006; 59.1% (55/93) vs. 43.7% (38/87), P = .038), and the level of nuclear ERα and ERβ in HCC tissue was inversely correlated with T stage, tumor size, and clinical staging (P < .05). Correlation analysis showed the expression level of klotho, which is positively correlated with that of nuclear ERα (r = 0.243, P = .019). Patients with klotho-positive tumors had longer survival than those with klotho-negative tumors (P = .002). Cox proportional hazards model analysis demonstrated that positive expression of klotho was an important factor indicating good prognosis (P = .003). CONCLUSION Klotho, partially regulated by ERα-mediated estrogen pathway, acts as a tumor suppressor and might be a novel biomarker candidate for predicting progression and prognosis in HCC patients.
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Affiliation(s)
- Shu Huang
- Department of Gastroenterology, The People’s Hospital of Lianshui, Huaian, China
| | - Wei Wang
- Department of Gastroenterology, The People’s Hospital of Lianshui, Huaian, China
| | - Yajun Cheng
- Department of Gastroenterology, The People’s Hospital of Lianshui, Huaian, China
| | - Jie Lin
- Medical Center for Digestive Diseases, The Second Affiliated Hospital, Nanjing Medical University, China
- Department of Gastroenterology, The Fourth Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Min Wang
- Digestive Endoscopy Department, The First Affiliated Hospital, Nanjing Medical University, Nanjing, China
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27
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Fujita-Yamashita M, Yamamoto K, Honda H, Hanayama Y, Tokumasu K, Nakano Y, Hasegawa K, Hagiya H, Obika M, Ogawa H, Otsuka F. Gender-Dependent Characteristics of Serum 1,25-Dihydroxyvitamin D/25-Hydroxyvitamin D Ratio for the Assessment of Bone Metabolism. Cureus 2021; 13:e18070. [PMID: 34671537 PMCID: PMC8521239 DOI: 10.7759/cureus.18070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2021] [Indexed: 12/04/2022] Open
Abstract
Objectives Vitamin D deficiency, which is common worldwide, increases the risks of falls and fractures and can lead to increased morbidity and mortality. However, the clinical utility and relevance of vitamin D activation remain unknown. The aim of the present study was to clarify the clinical usefulness of serum 1,25-dihydroxyvitamin D (1,25D)/25-hydroxyvitamin D (25D) ratio for assessment of the extent of bone metabolism. Methods We retrospectively screened data for 87 patients whose serum 1,25D and 25D levels were measured. Eight patients who were taking vitamin D preparations were excluded, and data for 79 patients (33 males and 46 females) were analyzed. Since menopausal status can be associated with serum vitamin D level, we divided the patients by gender and divided the female patients into two groups at the age of 50 years. Results The median serum 1,25D/25D ratio was significantly lower in males than in females, with the most considerable difference in all males [4.1 (interquartile range: 2.3-5.8) × 10-3] versus elderly females (aged ≧50 years) [7.9 (3.3-10.1) × 10-3). Main disorders were endocrine (30.6%), inflammatory (18.5%), and bone-related (16.7%) disorders. The ratios of serum 1,25D/25D had significant negative correlations with femoral dual-energy X-ray absorptiometry % young adult mean (DEXA %YAM) (R=-0.35) and lumbar DEXA %YAM (R=-0.32). Significant correlations were found between the 1,25D/25D ratio and serum levels of inorganic phosphate (iP), parathyroid hormone, and alkaline phosphatase (ALP). The 1,25D/25D ratio had gender-specific characteristics: the ratio was significantly correlated with age in males (R=-0.49), while it was significantly correlated with BMI in females (R=0.34). Conclusions The results of this study suggested that vitamin D activity is negatively correlated with bone mineral density, being reduced in aged males but enhanced in obese females.
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Affiliation(s)
- Manami Fujita-Yamashita
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JPN
| | - Koichiro Yamamoto
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JPN
| | - Hiroyuki Honda
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JPN
| | - Yoshihisa Hanayama
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JPN
| | - Kazuki Tokumasu
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JPN
| | - Yasuhiro Nakano
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JPN
| | - Kou Hasegawa
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JPN
| | - Hideharu Hagiya
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JPN
| | - Mikako Obika
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JPN
| | - Hiroko Ogawa
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JPN
| | - Fumio Otsuka
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JPN
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28
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Asenjo-Bueno A, Alcalde-Estévez E, El Assar M, Olmos G, Plaza P, Sosa P, Martínez-Miguel P, Ruiz-Torres MP, López-Ongil S. Hyperphosphatemia-Induced Oxidant/Antioxidant Imbalance Impairs Vascular Relaxation and Induces Inflammation and Fibrosis in Old Mice. Antioxidants (Basel) 2021; 10:antiox10081308. [PMID: 34439556 PMCID: PMC8389342 DOI: 10.3390/antiox10081308] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/16/2021] [Accepted: 08/17/2021] [Indexed: 02/06/2023] Open
Abstract
Aging impairs vascular function, but the mechanisms involved are unknown. The aim of this study was to analyze whether aging-related hyperphosphatemia is implied in this effect by elucidating the role of oxidative stress. C57BL6 mice that were aged 5 months (young) and 24 months (old), receiving a standard (0.6%) or low-phosphate (0.2%) diet, were used. Isolated mesenteric arteries from old mice showed diminished endothelium-dependent vascular relaxation by the down-regulation of NOS3 expression, increased inflammation and increased fibrosis in isolated aortas, compared to those isolated from young mice. In parallel, increased Nox4 expression and reduced Nrf2, Sod2-Mn and Gpx1 were found in the aortas from old mice, resulting in oxidant/antioxidant imbalance. The low-phosphate diet improved vascular function and oxidant/antioxidant balance in old mice. Mechanisms were analyzed in endothelial (EC) and vascular smooth muscle cells (SMCs) treated with the phosphate donor ß-glycerophosphate (BGP). In EC, BGP increased Nox4 expression and ROS production, which reduced NOS3 expression via NFκB. BGP also increased inflammation in EC. In SMC, BGP increased Collagen I and fibronectin expression by priming ROS production and NFκB activity. In conclusion, hyperphosphatemia reduced endothelium-dependent vascular relaxation and increased inflammation and vascular fibrosis through an impairment of oxidant/antioxidant balance in old mice. A low-phosphate diet achieved improvements in the vascular function in old mice.
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Affiliation(s)
- Ana Asenjo-Bueno
- Unidad de Investigación de la Fundación para la Investigación Biomédica del Hospital Universitario Príncipe de Asturias, Alcalá de Henares, 28805 Madrid, Spain; (A.A.-B.); (P.P.); (P.M.-M.)
- Departamento Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid, Spain; (E.A.-E.); (G.O.); (P.S.); (M.P.R.-T.)
| | - Elena Alcalde-Estévez
- Departamento Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid, Spain; (E.A.-E.); (G.O.); (P.S.); (M.P.R.-T.)
| | - Mariam El Assar
- Fundación para la Investigación Biomédica del Hospital Universitario de Getafe, Getafe, 28905 Madrid, Spain;
| | - Gemma Olmos
- Departamento Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid, Spain; (E.A.-E.); (G.O.); (P.S.); (M.P.R.-T.)
- Instituto Reina Sofía de Investigación Nefrológica (IRSIN) de la Fundación Renal Iñigo Álvarez de Toledo (FRIAT), 28003 Madrid, Spain
- Area 3-Fisiología y Fisiopatología Renal y Vascular del IRYCIS, 28046 Madrid, Spain
| | - Patricia Plaza
- Unidad de Investigación de la Fundación para la Investigación Biomédica del Hospital Universitario Príncipe de Asturias, Alcalá de Henares, 28805 Madrid, Spain; (A.A.-B.); (P.P.); (P.M.-M.)
| | - Patricia Sosa
- Departamento Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid, Spain; (E.A.-E.); (G.O.); (P.S.); (M.P.R.-T.)
| | - Patricia Martínez-Miguel
- Unidad de Investigación de la Fundación para la Investigación Biomédica del Hospital Universitario Príncipe de Asturias, Alcalá de Henares, 28805 Madrid, Spain; (A.A.-B.); (P.P.); (P.M.-M.)
- Servicio de Nefrología del Hospital Universitario Príncipe de Asturias, Alcalá de Henares, 28805 Madrid, Spain
| | - María Piedad Ruiz-Torres
- Departamento Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid, Spain; (E.A.-E.); (G.O.); (P.S.); (M.P.R.-T.)
- Instituto Reina Sofía de Investigación Nefrológica (IRSIN) de la Fundación Renal Iñigo Álvarez de Toledo (FRIAT), 28003 Madrid, Spain
- Area 3-Fisiología y Fisiopatología Renal y Vascular del IRYCIS, 28046 Madrid, Spain
| | - Susana López-Ongil
- Unidad de Investigación de la Fundación para la Investigación Biomédica del Hospital Universitario Príncipe de Asturias, Alcalá de Henares, 28805 Madrid, Spain; (A.A.-B.); (P.P.); (P.M.-M.)
- Instituto Reina Sofía de Investigación Nefrológica (IRSIN) de la Fundación Renal Iñigo Álvarez de Toledo (FRIAT), 28003 Madrid, Spain
- Area 3-Fisiología y Fisiopatología Renal y Vascular del IRYCIS, 28046 Madrid, Spain
- Correspondence: ; Tel.: +34-91-887-8100 (ext. 2604); Fax: +34-91-882-2674
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Gagan JM, Cao K, Zhang YA, Zhang J, Davidson TL, Pastor JV, Moe OW, Hsia CCW. Constitutive transgenic alpha-Klotho overexpression enhances resilience to and recovery from murine acute lung injury. Am J Physiol Lung Cell Mol Physiol 2021; 321:L736-L749. [PMID: 34346778 DOI: 10.1152/ajplung.00629.2020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
AIMS Normal lungs do not express alpha-Klotho (Klotho) protein but derive cytoprotection from circulating soluble Klotho. It is unclear whether chronic supranormal Klotho levels confer additional benefit. To address this, we tested the age-related effects of Klotho overexpression on acute lung injury (ALI) and recovery. METHODS Transgenic Klotho-overexpressing (Tg-Kl) and wild-type (WT) mice (2 and 6 months old) were exposed to hyperoxia (95% O2; 72 h) then returned to normoxia (21% O2; 24 h) (Hx-R). Control mice were kept in normoxia. Renal and serum Klotho, lung histology, and bronchoalveolar lavage fluid oxidative damage markers were assessed. Effects of hyperoxia were tested in human embryonic kidney cells stably expressing Klotho. A549 lung epithelial cells transfected with Klotho cDNA or vector were exposed to cigarette smoke; lactate dehydrogenase and double-strand DNA breaks were measured. RESULTS Serum Klotho decreased with age. Hyperoxia suppressed renal Klotho at both ages and serum Klotho at 2-months of age. Tg-Kl mice at both ages and 2-months-old WT mice survived Hx-R; 6-months-old Tg-Kl mice showed lower lung damage than age-matched WT mice. Hyperoxia directly inhibited Klotho expression and release in vitro; Klotho transfection attenuated cigarette smoke-induced cytotoxicity and DNA double-strand breaks in lung epithelial cells. CONCLUSIONS Young animals with chronic high baseline Klotho expression are more resistant to ALI. Chronic constitutive Klotho overexpression in older Tg-Kl animals attenuates hyperoxia-induced lung damage and improves survival and short-term recovery despite an acute reduction in serum Klotho level during injury. We conclude that chronic enhancement of Klotho expression increases resilience to ALI.
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Affiliation(s)
- Joshuah M Gagan
- Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Khoa Cao
- Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Yu-An Zhang
- Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Jianning Zhang
- Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Taylor L Davidson
- Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, The University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Johanne V Pastor
- Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, United States.,Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, The University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Orson W Moe
- Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, United States.,Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, The University of Texas Southwestern Medical Center, Dallas, TX, United States.,Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Connie C W Hsia
- Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, United States
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Abbasian N. Vascular Calcification Mechanisms: Updates and Renewed Insight into Signaling Pathways Involved in High Phosphate-Mediated Vascular Smooth Muscle Cell Calcification. Biomedicines 2021; 9:804. [PMID: 34356868 PMCID: PMC8301440 DOI: 10.3390/biomedicines9070804] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/04/2021] [Accepted: 07/09/2021] [Indexed: 12/18/2022] Open
Abstract
Vascular calcification (VC) is associated with aging, cardiovascular and renal diseases and results in poor morbidity and increased mortality. VC occurs in patients with chronic kidney disease (CKD), a condition that is associated with high serum phosphate (Pi) and severe cardiovascular consequences. High serum Pi level is related to some pathologies which affect the behaviour of vascular cells, including platelets, endothelial cells (ECs) and smooth muscle cells (SMCs), and plays a central role in promoting VC. VC is a complex, active and cell-mediated process involving the transdifferentiation of vascular SMCs to a bone-like phenotype, systemic inflammation, decreased anti-calcific events (loss of calcification inhibitors), loss in SMC lineage markers and enhanced pro-calcific microRNAs (miRs), an increased intracellular calcium level, apoptosis, aberrant DNA damage response (DDR) and senescence of vascular SMCs. This review gives a brief overview of the current knowledge of VC mechanisms with a particular focus on Pi-induced changes in the vascular wall important in promoting calcification. In addition to reviewing the main findings, this review also sheds light on directions for future research in this area and discusses emerging pathways such as Pi-regulated intracellular calcium signaling, epigenetics, oxidative DNA damage and senescence-mediated mechanisms that may play critical, yet to be explored, regulatory and druggable roles in limiting VC.
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Affiliation(s)
- Nima Abbasian
- School of Life and Medical Sciences, University of Hertfordshire, Hertfordshire AL10 9AB, UK
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31
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Tsuchiya K, Akihisa T. The Importance of Phosphate Control in Chronic Kidney Disease. Nutrients 2021; 13:nu13051670. [PMID: 34069053 PMCID: PMC8156430 DOI: 10.3390/nu13051670] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/06/2021] [Accepted: 05/12/2021] [Indexed: 12/12/2022] Open
Abstract
A series of problems including osteopathy, abnormal serum data, and vascular calcification associated with chronic kidney disease (CKD) are now collectively called CKD-mineral bone disease (CKD-MBD). The pathophysiology of CKD-MBD is becoming clear with the emerging of αKlotho, originally identified as a progeria-causing protein, and bone-derived phosphaturic fibroblast growth factor 23 (FGF23) as associated factors. Meanwhile, compared with calcium and parathyroid hormone, which have long been linked with CKD-MBD, phosphate is now attracting more attention because of its association with complications and outcomes. Incidentally, as the pivotal roles of FGF23 and αKlotho in phosphate metabolism have been unveiled, how phosphate metabolism and hyperphosphatemia are involved in CKD-MBD and how they can be clinically treated have become of great interest. Thus, the aim of this review is reconsider CKD-MBD from the viewpoint of phosphorus, its involvement in the pathophysiology, causing complications, therapeutic approach based on the clinical evidence, and clarifying the importance of phosphorus management.
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Affiliation(s)
- Ken Tsuchiya
- Department of Blood Purification, Tokyo Women’s Medical University, Tokyo 162-8666, Japan
- Correspondence:
| | - Taro Akihisa
- Department of Nephrology, Tokyo Women’s Medical University, Tokyo 162-8666, Japan;
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32
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Kuro-O M. Phosphate as a Pathogen of Arteriosclerosis and Aging. J Atheroscler Thromb 2021; 28:203-213. [PMID: 33028781 PMCID: PMC8048948 DOI: 10.5551/jat.rv17045] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 09/04/2020] [Indexed: 02/06/2023] Open
Abstract
During the evolution of skeletons, terrestrial vertebrates acquired strong bones made of calcium-phosphate. By keeping the extracellular fluid in a supersaturated condition regarding calcium and phosphate ions, they created the bone when and where they wanted simply by providing a cue for precipitation. To secure this strategy, they acquired a novel endocrine system to strictly control the extracellular phosphate concentration. In response to phosphate intake, fibroblast growth factor-23 (FGF23) is secreted from the bone and acts on the kidney through binding to its receptor Klotho to increase urinary phosphate excretion, thereby maintaining phosphate homeostasis. The FGF23-Klotho endocrine system, when disrupted in mice, results in hyperphosphatemia and vascular calcification. Besides, mice lacking Klotho or FGF23 suffer from complex aging-like phenotypes, which are alleviated by placing them on a low- phosphate diet, indicating that phosphate is primarily responsible for the accelerated aging. Phosphate acquires the ability to induce cell damage and inflammation when precipitated with calcium. In the blood, calcium-phosphate crystals are adsorbed by serum protein fetuin-A and prevented from growing into large precipitates. Consequently, nanoparticles that comprised calcium-phosphate crystals and fetuin-A, termed calciprotein particles (CPPs), are generated and dispersed as colloids. CPPs increase in the blood with an increase in serum phosphate and age. Circulating CPP levels correlate positively with vascular stiffness and chronic non-infectious inflammation, raising the possibility that CPPs may be an endogenous pro-aging factor. Terrestrial vertebrates with the bone made of calcium- phosphate may be destined to age due to calcium-phosphate in the blood.
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Affiliation(s)
- Makoto Kuro-O
- Division of Anti-aging Medicine, Center for Molecular Medicine, Jichi Medical University
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33
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Chacar FC, Kogika MM, Zafalon RVA, Brunetto MA. Vitamin D Metabolism and Its Role in Mineral and Bone Disorders in Chronic Kidney Disease in Humans, Dogs and Cats. Metabolites 2020; 10:E499. [PMID: 33291777 PMCID: PMC7761928 DOI: 10.3390/metabo10120499] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/21/2020] [Accepted: 11/24/2020] [Indexed: 11/17/2022] Open
Abstract
Some differences regarding Vitamin D metabolism are described in dogs and cats in comparison with humans, which may be explained by an evolutionary drive among these species. Similarly, vitamin D is one of the most important regulators of mineral metabolism in dogs and cats, as well as in humans. Mineral metabolism is intrinsically related to bone metabolism, thus disturbances in vitamin D have been implicated in the development of chronic kidney disease mineral and bone disorders (CKD-MBD) in people, in addition to dogs and cats. Vitamin D deficiency may be associated with Renal Secondary Hyperparathyroidism (RSHPT), which is the most common mineral disorder in later stages of CKD in dogs and cats. Herein, we review the peculiarities of vitamin D metabolism in these species in comparison with humans, and the role of vitamin D disturbances in the development of CKD-MBD among dogs, cats, and people. Comparative studies may offer some evidence to help further research about vitamin D metabolism and bone disorders in CKD.
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Affiliation(s)
- Fernanda C. Chacar
- Department of Internal Medicine, Federal Institute of Education, Science and Technology of South of Minas Gerais (IFSULDEMINAS), Muzambinho 37890-000, Brazil;
| | - Márcia M. Kogika
- Department of Internal Medicine, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo 05508-270, Brazil;
| | - Rafael V. A. Zafalon
- Pet Nutrology Research Center, Nutrition and Production Department, School of Veterinary Medicine and Animal Science, University of São Paulo, Pirassununga 13635-900, Brazil;
| | - Marcio A. Brunetto
- Pet Nutrology Research Center, Nutrition and Production Department, School of Veterinary Medicine and Animal Science, University of São Paulo, Pirassununga 13635-900, Brazil;
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34
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Su C, Meng L, Trooskin SZ, Shapses SA, He Y, Al-Dayyeni A, Wang X. Serum Klotho levels in primary hyperparathyroidism patients before and after parathyroidectomy. Endocrine 2020; 70:421-425. [PMID: 32710436 DOI: 10.1007/s12020-020-02427-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 07/17/2020] [Indexed: 02/05/2023]
Abstract
PURPOSE To investigate Klotho level and its association with biochemical indices of primary hyperparathyroidism (PHPT). METHODS Fifty PHPT patients and fifty-two age- and body mass index-(BMI) matched healthy control subjects were recruited. In addition, twenty-five PHPT patients underwent parathyroidectomy (PTX) and had 4-month follow-up visits. Intact parathyroid hormone (iPTH), 25-hydroxyvitamin D [25(OH)D], calcium, albumin, corrected calcium, and Klotho levels were determined. RESULTS There was no significant difference in age and BMI between PHPT subjects and controls (p > 0.05). PHPT patients had Klotho levels (15.4 ± 1.2 ng/mL) about 23% higher compared with those of the controls (11.9 ± 0.8 ng/mL), but this difference was not significant (p = 0.063). However, postmenopausal PHPT patients had 45% higher Klotho levels (17.6 ± 1.5 ng/ml) compared with postmenopausal controls (12.1 ± 0.9 ng/mL, p = 0.008). For postmenopausal subjects, Klotho levels had positive correlation with levels of iPTH (r = 0.25, p = 0.026) and corrected calcium (r = 0.34, p = 0.003), but negative correlation with 25(OH)D (r = -0.23, p = 0.042). After PTX, levels of iPTH and corrected calcium decreased and 25(OH)D levels increased to normal range (p < 0.001). However, there was no significant change in Klotho levels after a 4-month follow-up. CONCLUSIONS Serum Klotho levels are higher in postmenopausal PHPT patients than in healthy postmenopausal control subjects. The etiology of elevated Klotho level and its clinical significance requires further investigation.
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Affiliation(s)
- Chi Su
- Division of Endocrinology, Metabolism & Nutrition, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Lingqiong Meng
- Department of Nutritional Sciences, School of Environmental and Biological Sciences, Rutgers University, New Brunswick, NJ, USA
| | - Stanley Z Trooskin
- Division of General Surgery, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Sue A Shapses
- Department of Nutritional Sciences, School of Environmental and Biological Sciences, Rutgers University, New Brunswick, NJ, USA
| | - Yuling He
- Division of Endocrinology, Metabolism & Nutrition, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Aseel Al-Dayyeni
- Division of Endocrinology, Metabolism & Nutrition, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Xiangbing Wang
- Division of Endocrinology, Metabolism & Nutrition, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA.
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Navarro‐García JA, Rueda A, Romero‐García T, Aceves‐Ripoll J, Rodríguez‐Sánchez E, González‐Lafuente L, Zaragoza C, Fernández‐Velasco M, Kuro‐o M, Ruilope LM, Ruiz‐Hurtado G. Enhanced Klotho availability protects against cardiac dysfunction induced by uraemic cardiomyopathy by regulating Ca 2+ handling. Br J Pharmacol 2020; 177:4701-4719. [PMID: 32830863 PMCID: PMC7520447 DOI: 10.1111/bph.15235] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 07/23/2020] [Accepted: 08/05/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND PURPOSE Klotho is a membrane-bound or soluble protein, originally identified as an age-suppressing factor and regulator of mineral metabolism. Klotho deficiency is associated with the development of renal disease, but its role in cardiac function in the context of uraemic cardiomyopathy is unknown. EXPERIMENTAL APPROACH We explored the effects of Klotho on cardiac Ca2+ cycling. We analysed Ca2+ handling in adult cardiomyocytes from Klotho-deficient (kl/kl) mice and from a murine model of 5/6 nephrectomy (Nfx). We also studied the effect of exogenous Klotho supplementation, by chronic recombinant Klotho treatment, or endogenous Klotho overexpression, using transgenic mice overexpressing Klotho (Tg-Kl), on uraemic cardiomyopathy. Hearts from Nfx mice were used to study Ca2+ sensitivity of ryanodine receptors and their phosphorylation state. KEY RESULTS Cardiomyocytes from kl/kl mice showed decreased amplitude of intracellular Ca2+ transients and cellular shortening together with an increase in pro-arrhythmic Ca2+ events compared with cells from wild-type mice. Cardiomyocytes from Nfx mice exhibited the same impairment in Ca2+ cycling as kl/kl mice. Changes in Nfx cardiomyocytes were explained by higher sensitivity of ryanodine receptors to Ca2+ and their increased phosphorylation at the calmodulin kinase type II and protein kinase A sites. Ca2+ mishandling in Nfx-treated mice was fully prevented by chronic recombinant Klotho administration or transgenic Klotho overexpression. CONCLUSIONS AND IMPLICATIONS Klotho emerges as an attractive therapeutic tool to improve cardiac Ca2+ mishandling observed in uraemic cardiomyopathy. Strategies that improve Klotho availability are good candidates to protect the heart from functional cardiac alterations in renal disease.
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Affiliation(s)
- José Alberto Navarro‐García
- Cardiorenal Translational LaboratoryInstitute of Research i+12, Hospital Universitario 12 de OctubreMadridSpain
| | - Angélica Rueda
- Departamento de BioquímicaCentro de Investigación y de Estudios Avanzados del IPNMéxico CityDFMexico
| | - Tatiana Romero‐García
- Departamento de BioquímicaCentro de Investigación y de Estudios Avanzados del IPNMéxico CityDFMexico
| | - Jennifer Aceves‐Ripoll
- Cardiorenal Translational LaboratoryInstitute of Research i+12, Hospital Universitario 12 de OctubreMadridSpain
| | - Elena Rodríguez‐Sánchez
- Cardiorenal Translational LaboratoryInstitute of Research i+12, Hospital Universitario 12 de OctubreMadridSpain
| | - Laura González‐Lafuente
- Cardiorenal Translational LaboratoryInstitute of Research i+12, Hospital Universitario 12 de OctubreMadridSpain
| | - Carlos Zaragoza
- Department of CardiologyUnidad de Investigación Mixta Universidad Francisco de Vitoria/Hospital Ramon y Cajal (IRYCIS)MadridSpain
| | | | - Makoto Kuro‐o
- Division of Anti‐ageing Medicine, Centre for Molecular MedicineJichi Medical UniversityShimotsukeTochigiJapan
| | - Luis M. Ruilope
- Cardiorenal Translational LaboratoryInstitute of Research i+12, Hospital Universitario 12 de OctubreMadridSpain
- CIBER‐CVHospital Universitario 12 de OctubreMadridSpain
- School of Doctoral Studies and ResearchEuropean University of MadridMadridSpain
| | - Gema Ruiz‐Hurtado
- Cardiorenal Translational LaboratoryInstitute of Research i+12, Hospital Universitario 12 de OctubreMadridSpain
- CIBER‐CVHospital Universitario 12 de OctubreMadridSpain
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Frassetto LA, Sebastian A, DuBose TD. How metabolic acidosis and kidney disease may accelerate the aging process. Eur J Clin Nutr 2020; 74:27-32. [PMID: 32873954 DOI: 10.1038/s41430-020-0693-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Consuming a lower acid (and particularly lower phosphate) diet and/or supplementing the diet with base precursors, such as bicarbonate, might have a number of mitigating effects on the aging process. These include: (1) slowing progression of fibrosis by reduction of high endogenous acid production to preserve net acid excretion and minimize the degree of systemic acidosis; (2) avoiding the downregulation of klotho, a membrane and soluble factor associated with aging. Klotho declines when constant high dietary phosphate intake leads to an increase in FGF23 production; and (3) increasing activity of the enzyme telomerase, an important factor in maintaining telomere length, another factor associated with longer lifespan. Current evidence is based on studies in invertebrate and small animal models. These results, and extrapolations of associated human studies, suggest that low acid-producing diets, or neutralization of the low grade metabolic acidosis seen in humans with age-related renal dysfunction could potentially lead to a longer, healthier lifespan.
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TOMŞA AM, ALEXA AL, RĂCHIŞAN AL, PICOŞ A, PICOŞ AM, CIUMĂRNEAN L. Skeletal manifestations in end-stage renal disease patients and relation to FGF23 and Klotho. BALNEO RESEARCH JOURNAL 2020. [DOI: 10.12680/balneo.2020.252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Chronic kidney disease affects patients of all ages and, as it progresses, it greatly affects their lives, especially with the complications it causes. One major complication is renal osteodystrophy (ROD) which starts to develop from the early stages of the disease, but becomes most apparent in patients in need of renal replacement therapy. Diagnosing ROD in the early stages remains a challenge, which brings up the need to find novel biomarkers. Studies are focusing on the role of fibroblast growth factor 23 and Klotho in the bone and mineral homeostasis, but the results are conflicting. ROD remains a major complication in CKD patients, therefore we need to gain a better understanding from the pathophysiological point of view, in order to be able to adjust the medical therapy.
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Affiliation(s)
- Anamaria Magdalena TOMŞA
- 1. “Iuliu Hatieganu” University of Medicine and Pharmacy, Department Mother and Child, 2nd Clinic of Pediatrics, Cluj-Napoca, Romania
| | - Alexandru Leonard ALEXA
- “Iuliu Hatieganu” University of Medicine and Pharmacy, Department of Surgery, Cluj-Napoca, Romania
| | - Andreea Liana RĂCHIŞAN
- 1. “Iuliu Hatieganu” University of Medicine and Pharmacy, Department Mother and Child, 2nd Clinic of Pediatrics, Cluj-Napoca, Romania
| | - Andrei PICOŞ
- 3. “Iuliu Hatieganu” University of Medicine and Pharmacy, Department of Prosthetics, Cluj-Napoca, Romania
| | - Alina Monica PICOŞ
- “Iuliu Hatieganu” University of Medicine and Pharmacy, Department of Oral Rehabilitation, Cluj-Napoca, Romania
| | - Lorena CIUMĂRNEAN
- 5. “Iuliu Hatieganu” University of Medicine and Pharmacy, Department of Internal Medicine, Cluj-Napoca, Romania
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Buchanan S, Combet E, Stenvinkel P, Shiels PG. Klotho, Aging, and the Failing Kidney. Front Endocrinol (Lausanne) 2020; 11:560. [PMID: 32982966 PMCID: PMC7481361 DOI: 10.3389/fendo.2020.00560] [Citation(s) in RCA: 136] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 07/09/2020] [Indexed: 12/11/2022] Open
Abstract
Klotho has been recognized as a gene involved in the aging process in mammals for over 30 years, where it regulates phosphate homeostasis and the activity of members of the fibroblast growth factor (FGF) family. The α-Klotho protein is the receptor for Fibroblast Growth Factor-23 (FGF23), regulating phosphate homeostasis and vitamin D metabolism. Phosphate toxicity is a hallmark of mammalian aging and correlates with diminution of Klotho levels with increasing age. As such, modulation of Klotho activity is an attractive target for therapeutic intervention in the diseasome of aging; in particular for chronic kidney disease (CKD), where Klotho has been implicated directly in the pathophysiology. A range of senotherapeutic strategies have been developed to directly or indirectly influence Klotho expression, with varying degrees of success. These include administration of exogenous Klotho, synthetic and natural Klotho agonists and indirect approaches, via modulation of the foodome and the gut microbiota. All these approaches have significant potential to mitigate loss of physiological function and resilience accompanying old age and to improve outcomes within the diseasome of aging.
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Affiliation(s)
- Sarah Buchanan
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Emilie Combet
- School of Medicine, Dentistry & Nursing, Human Nutrition, Glasgow Royal Infirmary, Glasgow, United Kingdom
| | - Peter Stenvinkel
- Division of Renal Medicine M99, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Paul G. Shiels
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
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Machado A, Pouzolles M, Gailhac S, Fritz V, Craveiro M, López-Sánchez U, Kondo T, Pala F, Bosticardo M, Notarangelo LD, Petit V, Taylor N, Zimmermann VS. Phosphate Transporter Profiles in Murine and Human Thymi Identify Thymocytes at Distinct Stages of Differentiation. Front Immunol 2020; 11:1562. [PMID: 32793218 PMCID: PMC7387685 DOI: 10.3389/fimmu.2020.01562] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 06/15/2020] [Indexed: 12/22/2022] Open
Abstract
Thymocyte differentiation is dependent on the availability and transport of metabolites in the thymus niche. As expression of metabolite transporters is a rate-limiting step in nutrient utilization, cell surface transporter levels generally reflect the cell's metabolic state. The GLUT1 glucose transporter is upregulated on actively dividing thymocytes, identifying thymocytes with an increased metabolism. However, it is not clear whether transporters of essential elements such as phosphate are modulated during thymocyte differentiation. While PiT1 and PiT2 are both phosphate transporters in the SLC20 family, we show here that they exhibit distinct expression profiles on both murine and human thymocytes. PiT2 expression distinguishes thymocytes with high metabolic activity, identifying immature murine double negative (CD4−CD8−) DN3b and DN4 thymocyte blasts as well as immature single positive (ISP) CD8 thymocytes. Notably, the absence of PiT2 expression on RAG2-deficient thymocytes, blocked at the DN3a stage, strongly suggests that high PiT2 expression is restricted to thymocytes having undergone a productive TCRβ rearrangement at the DN3a/DN3b transition. Similarly, in the human thymus, PiT2 was upregulated on early post-β selection CD4+ISP and TCRαβ−CD4hiDP thymocytes co-expressing the CD71 transferrin receptor, a marker of metabolic activity. In marked contrast, expression of the PiT1 phosphate importer was detected on mature CD3+ murine and human thymocytes. Notably, PiT1 expression on CD3+DN thymocytes was identified as a biomarker of an aging thymus, increasing from 8.4 ± 1.5% to 42.4 ± 9.4% by 1 year of age (p < 0.0001). We identified these cells as TCRγδ and, most significantly, NKT, representing 77 ± 9% of PiT1+DN thymocytes by 1 year of age (p < 0.001). Thus, metabolic activity and thymic aging are associated with distinct expression profiles of the PiT1 and PiT2 phosphate transporters.
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Affiliation(s)
- Alice Machado
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, United States.,Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Marie Pouzolles
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, United States
| | - Sarah Gailhac
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Vanessa Fritz
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Marco Craveiro
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Uriel López-Sánchez
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Taisuke Kondo
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, United States
| | - Francesca Pala
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, United States
| | - Marita Bosticardo
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, United States
| | - Luigi D Notarangelo
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, United States
| | | | - Naomi Taylor
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, United States.,Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Valérie S Zimmermann
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, United States.,Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
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Yang ZY, Kao TW, Peng TC, Chen YY, Yang HF, Wu CJ, Chen WL. Examining the association between serum phosphate levels and leukocyte telomere length. Sci Rep 2020; 10:5438. [PMID: 32214202 PMCID: PMC7096403 DOI: 10.1038/s41598-020-62359-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 03/10/2020] [Indexed: 12/24/2022] Open
Abstract
Accelerated telomere attrition is related to various diseases, and multiple factors have been reported to influence telomere length. However, little attention has focused on the relationship between serum phosphate levels and mean telomere length. The purpose of this study was to explore the relationship between serum phosphate levels and mean telomere length in the US general population. A total of 7,817 participants from the 1999–2002 NHANES were included. The association between serum phosphate levels and mean telomere length was investigated using regression models. A remarkably positive relationship between serum phosphate levels and mean telomere length emerged after adjustments were made for covariates. The adjusted β coefficient of serum phosphate levels for mean telomere length was 0.038 (95% confidence intervals (CIs), 0.022 to 0.095, p = 0.002). A longer telomere length was observed in participants with serum phosphate levels in the highest quartiles, and a dose-dependent association was observed. Our study demonstrated that higher quartiles of phosphate had a remarkable correlation with longer telomere length.
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Affiliation(s)
- Zhe-Yu Yang
- Department of General Medicine, Tri-Service General Hospital, and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China.,Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Tung-Wei Kao
- Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China.,Division of Geriatric Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China.,Graduate Institute of Clinical Medical, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China
| | - Tao-Chun Peng
- Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China.,Division of Geriatric Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Yuan-Yuei Chen
- Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China.,Department of Pathology, Tri-Service General Hospital, and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Hui-Fang Yang
- Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China.,Division of Geriatric Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Chen-Jung Wu
- Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China.,Division of Family Medicine, Department of Community Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan, Republic of China
| | - Wei-Liang Chen
- Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China. .,Division of Geriatric Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China.
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Han X, Cai C, Xiao Z, Quarles LD. FGF23 induced left ventricular hypertrophy mediated by FGFR4 signaling in the myocardium is attenuated by soluble Klotho in mice. J Mol Cell Cardiol 2020; 138:66-74. [PMID: 31758962 PMCID: PMC7195870 DOI: 10.1016/j.yjmcc.2019.11.149] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 11/12/2019] [Accepted: 11/14/2019] [Indexed: 12/15/2022]
Abstract
There is controversy regarding whether excess FGF23 causes left ventricular hypertrophy (LVH) directly through activation of fibroblast growth factor receptor 4 (FGFR4) in cardiomyocytes or indirectly through reductions in soluble Klotho (sK). We investigated the respective roles of myocardial FGFR4 and sKL in mediating FGF23-induced LVH using mouse genetic and pharmacological approaches. To investigate a direct role of myocardial FGFR4 in mediating the cardiotoxic effects of excess circulating FGF23, we administered rFGF23 to mice with cardiac-specific loss of FGFR4 (FGFR4 heart-cKO). We tested a model of sKL deficiency, hypertension and LVH created by the conditional deletion of FGFR1 in the renal distal tubule (FGFR1DT cKO mice). The cardioprotective effects of sKL in both mouse models was assessed by the systemic administration of recombinant sKL. We confirmed that FGF23 treatment activates PLCγ in the heart and induces LVH in the absence of membrane α-Klotho. Conditional deletion of FGFR4 in the myocardium prevented rFGF23-induced LVH in mice, establishing direct cardiotoxicity of FGF23 through activation of FGFR4. Recombinant sKL administration prevented LVH, but not HTN, in FGFR1DT cKO mice, consistent with direct cardioprotective effects. Co-administration of recombinant sKL with FGF23 in culture inhibited rFGF23-induced p-PLCγ signaling. Thus, FGF23 ability to include LVH represents a balance between FGF23 direct cardiac activation of FGFR4 and the modulating effects of circulating sKL to alter FGF23-dependent myocardial signaling pathways.
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Affiliation(s)
- Xiaobin Han
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, United States of America
| | - Chun Cai
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, United States of America
| | - Zhousheng Xiao
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, United States of America
| | - L Darryl Quarles
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, United States of America.
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Abstract
The Klotho proteins, αKlotho and βKlotho, are essential components of endocrine fibroblast growth factor (FGF) receptor complexes, as they are required for the high-affinity binding of FGF19, FGF21 and FGF23 to their cognate FGF receptors (FGFRs). Collectively, these proteins form a unique endocrine system that governs multiple metabolic processes in mammals. FGF19 is a satiety hormone that is secreted from the intestine on ingestion of food and binds the βKlotho-FGFR4 complex in hepatocytes to promote metabolic responses to feeding. By contrast, under fasting conditions, the liver secretes the starvation hormone FGF21, which induces metabolic responses to fasting and stress responses through the activation of the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system following binding to the βKlotho-FGFR1c complex in adipocytes and the suprachiasmatic nucleus, respectively. Finally, FGF23 is secreted by osteocytes in response to phosphate intake and binds to αKlotho-FGFR complexes, which are expressed most abundantly in renal tubules, to regulate mineral metabolism. Growing evidence suggests that the FGF-Klotho endocrine system also has a crucial role in the pathophysiology of ageing-related disorders, including diabetes, cancer, arteriosclerosis and chronic kidney disease. Therefore, targeting the FGF-Klotho endocrine axes might have therapeutic benefit in multiple systems; investigation of the crystal structures of FGF-Klotho-FGFR complexes is paving the way for the development of drugs that can regulate these axes.
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Affiliation(s)
- Makoto Kuro-O
- Division of Anti-aging Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan. .,Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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Jin XH, Pi LQ, Lee WS. Expression Pattern and Role of Klotho in Human Hair Follicles. Ann Dermatol 2019; 31:511-517. [PMID: 33911642 PMCID: PMC7992569 DOI: 10.5021/ad.2019.31.5.511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 04/22/2019] [Accepted: 05/02/2019] [Indexed: 11/24/2022] Open
Abstract
Background Klotho protein plays a pivotal role in aging regulation. However, it is unclear whether klotho is expressed in human hair follicles and is correlated with hair growth. Objective The purpose of this study was to determine the expression pattern and role of klotho in human hair follicles. Methods We examined the klotho expression patterns in human hair follicles from young and aged donors. Furthermore, we examined the functional roles of klotho on human hair growth using klotho siRNA and klotho recombinant protein. Results Interestingly, klotho was expressed in human hair follicles at both gene and protein levels. In hair follicles, prominent klotho expression was mainly observed in the outermost regions of the outer root sheath and hair bulb matrix cells. Quantification of klotho protein expression in young and aged donors showed that klotho expression decreased with aging. In human hair follicle organ culture, klotho silencing promoted premature catagen induction and inhibited human hair growth. Otherwise, klotho protein prolonged human hair growth. Conclusion These results indicate that klotho might be an important regulatory factor for human hair growth and hair cycle change.
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Affiliation(s)
- Xing-Hai Jin
- Department of Dermatology and Institute of Hair and Cosmetic Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Long-Quan Pi
- Department of Dermatology and Institute of Hair and Cosmetic Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Dermatology, Affiliated Hospital of Yanbian University, Yanji, China
| | - Won-Soo Lee
- Department of Dermatology and Institute of Hair and Cosmetic Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
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Kritmetapak K, Pongchaiyakul C. Parathyroid Hormone Measurement in Chronic Kidney Disease: From Basics to Clinical Implications. Int J Nephrol 2019; 2019:5496710. [PMID: 31637056 PMCID: PMC6766083 DOI: 10.1155/2019/5496710] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 09/04/2019] [Indexed: 11/18/2022] Open
Abstract
Accurate measurement of parathyroid hormone (PTH) is crucial for therapeutic decision-making in patients with chronic kidney disease-mineral and bone disorder (CKD-MBD). The second-generation PTH assays, often referred to as "intact PTH" assays, are the current standard and most available assays in clinical practice. However, intact PTH assays measure both full-length biologically active PTH and heterogeneous PTH fragments in the circulation, providing the equivocal value of PTH measurement in patients with CKD-MBD. Due to the variability of PTH assays, preanalytical sample errors, and the phenomenon of end-organ PTH hyporesponsiveness, current CKD-MBD guidelines recommend a wide range for serum PTH targets (2-9 the upper normal limit of the intact PTH assay) in dialysis patients to diminish the risk of developing adynamic bone disease. Nevertheless, a sizeable proportion of CKD patients still experience renal osteodystrophy despite having serum PTH levels within the recommended range. The primary cause of this inconsistency is the analytical interference of various PTH fragments and oxidized PTH forms that considerably accumulate in CKD patients. Therefore, a new mass spectrometry-based assay, which is capable of specifically measuring the whole spectra of PTH fragments, can potentially improve diagnostic accuracy for renal osteodystrophy. However, the effects of different PTH fragments on bone metabolism, vascular calcification, and mortality in CKD patients warrant further research.
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Affiliation(s)
- Kittrawee Kritmetapak
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Chatlert Pongchaiyakul
- Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
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45
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The predictive value of Klotho polymorphism, in addition to classical markers of CKD-MBD, for left ventricular hypertrophy in haemodialysis patients. Int Urol Nephrol 2019; 51:1425-1433. [DOI: 10.1007/s11255-019-02193-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Accepted: 06/04/2019] [Indexed: 10/26/2022]
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Ferreira D, de Bragança AC, Volpini RA, Shimizu MHM, Gois PHF, Girardi ACC, Seguro AC, Canale D. Vitamin D deficiency is a potential risk factor for lipid Amphotericin B nephrotoxicity. PLoS Negl Trop Dis 2019; 13:e0007567. [PMID: 31295336 PMCID: PMC6622473 DOI: 10.1371/journal.pntd.0007567] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 06/20/2019] [Indexed: 12/21/2022] Open
Abstract
Invasive fungal infections (IFI) is a worldwide serious health problem and Amphotericin B (AmB) has been considered the drug of choice for IFI treatment. Despite its efficacy, clinical use of AmB has been associated with renal toxicity. Some lines of evidence have shown that an extemporaneous lipid emulsion preparation of AmB (AmB/LE) was able to attenuate nephrotoxicity, presenting similar benefits at a lower cost. Studies have been demonstrating that hypovitaminosis D may hasten the progression of kidney disease and reflect on a worse prognosis in cases of drug-induced nephrotoxicity. In view of the high worldwide incidence of hypovitaminosis D, the aim of this study was to investigate whether vitamin D deficiency may induce AmB/LE-related nephrotoxicity. Wistar rats were divided into four groups: control, received a standard diet for 34 days; AmB/LE, received a standard diet for 34 days and AmB/LE (5 mg/kg/day) intraperitoneally in the last 4 days; VDD, received a vitamin D-free diet for 34 days; and VDD+AmB/LE, received a vitamin D-free diet for 34 days and AmB/LE as described. At the end of the protocol, animals were euthanized and blood, urine and renal tissue samples were collected in order to evaluate AmB/LE effects on renal function and morphology. Association of AmB/LE and vitamin D deficiency led to diminished glomerular filtration rate and increased tubular injury, evidenced by reduced renal protein expression of NaPi-IIa and TRPM6 leading to hyperphosphaturia / hypermagnesuria. VDD+AmB/LE rats also presented alterations in the PTH-Klotho-FGF-23 signaling axis, urinary concentrating defect and hypertension, probably due to an inappropriate activation of the renin-angiotensin-aldosterone system. Hence, it is important to monitor vitamin D levels in AmB/LE treated patients, since vitamin D deficiency induces AmB/LE nephrotoxicity. Amphotericin B (AmB) is the treatment of choice for systemic fungal infections. Despite its efficacy, clinical use of AmB has been associated with renal toxicity. In an attempt to improve the therapeutic effect and to reduce adverse reactions, lipid formulations of AmB were developed. Among these formulations, an in-house lipid emulsion preparation of AmB (AmB/LE) is a lower cost alternative with similar benefits. Furthermore, vitamin D is an essential nutrient for the regulation of several physiological activities. Hence, vitamin D deficiency or insufficiency can contribute to the progression of diseases and increase the risk of chronic illnesses as well. Nowadays, VDD is a health problem worldwide and its prevalence in general population is high, including the sunny and industrialized countries, where vitamin D supplementation has been successfully implemented. Thus, it is essential to monitor vitamin D levels in both patients treated with conventional or lipid formulations of AmB in order to ensure a better prognosis in the development of renal diseases.
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Affiliation(s)
- Daniela Ferreira
- Laboratorio de Investigacao Medica 12 (LIM12), Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Ana Carolina de Bragança
- Laboratorio de Investigacao Medica 12 (LIM12), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Rildo Aparecido Volpini
- Laboratorio de Investigacao Medica 12 (LIM12), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | | | - Pedro Henrique França Gois
- Laboratorio de Investigacao Medica 12 (LIM12), Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | | | - Antonio Carlos Seguro
- Laboratorio de Investigacao Medica 12 (LIM12), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Daniele Canale
- Laboratorio de Investigacao Medica 12 (LIM12), Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
- * E-mail:
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Holditch SJ, Brown CN, Lombardi AM, Nguyen KN, Edelstein CL. Recent Advances in Models, Mechanisms, Biomarkers, and Interventions in Cisplatin-Induced Acute Kidney Injury. Int J Mol Sci 2019; 20:ijms20123011. [PMID: 31226747 PMCID: PMC6627318 DOI: 10.3390/ijms20123011] [Citation(s) in RCA: 251] [Impact Index Per Article: 41.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 05/31/2019] [Accepted: 06/12/2019] [Indexed: 12/14/2022] Open
Abstract
Cisplatin is a widely used chemotherapeutic agent used to treat solid tumours, such as ovarian, head and neck, and testicular germ cell. A known complication of cisplatin administration is acute kidney injury (AKI). The development of effective tumour interventions with reduced nephrotoxicity relies heavily on understanding the molecular pathophysiology of cisplatin-induced AKI. Rodent models have provided mechanistic insight into the pathophysiology of cisplatin-induced AKI. In the subsequent review, we provide a detailed discussion of recent advances in the cisplatin-induced AKI phenotype, principal mechanistic findings of injury and therapy, and pre-clinical use of AKI rodent models. Cisplatin-induced AKI murine models faithfully develop gross manifestations of clinical AKI such as decreased kidney function, increased expression of tubular injury biomarkers, and tubular injury evident by histology. Pathways involved in AKI include apoptosis, necrosis, inflammation, and increased oxidative stress, ultimately providing a translational platform for testing the therapeutic efficacy of potential interventions. This review provides a discussion of the foundation laid by cisplatin-induced AKI rodent models for our current understanding of AKI molecular pathophysiology.
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Affiliation(s)
- Sara J Holditch
- Division of Renal Diseases and Hypertension, University of Colorado at Denver, Box C281, 12700 East, 19th Ave, Aurora, CO 80045, USA.
| | - Carolyn N Brown
- Division of Renal Diseases and Hypertension, University of Colorado at Denver, Box C281, 12700 East, 19th Ave, Aurora, CO 80045, USA.
| | - Andrew M Lombardi
- Division of Renal Diseases and Hypertension, University of Colorado at Denver, Box C281, 12700 East, 19th Ave, Aurora, CO 80045, USA.
| | - Khoa N Nguyen
- Division of Renal Diseases and Hypertension, University of Colorado at Denver, Box C281, 12700 East, 19th Ave, Aurora, CO 80045, USA.
| | - Charles L Edelstein
- Division of Renal Diseases and Hypertension, University of Colorado at Denver, Box C281, 12700 East, 19th Ave, Aurora, CO 80045, USA.
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Voelkl J, Lang F, Eckardt KU, Amann K, Kuro-O M, Pasch A, Pieske B, Alesutan I. Signaling pathways involved in vascular smooth muscle cell calcification during hyperphosphatemia. Cell Mol Life Sci 2019; 76:2077-2091. [PMID: 30887097 PMCID: PMC6502780 DOI: 10.1007/s00018-019-03054-z] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Revised: 02/13/2019] [Accepted: 02/21/2019] [Indexed: 02/06/2023]
Abstract
Medial vascular calcification has emerged as a putative key factor contributing to the excessive cardiovascular mortality of patients with chronic kidney disease (CKD). Hyperphosphatemia is considered a decisive determinant of vascular calcification in CKD. A critical role in initiation and progression of vascular calcification during elevated phosphate conditions is attributed to vascular smooth muscle cells (VSMCs), which are able to change their phenotype into osteo-/chondroblasts-like cells. These transdifferentiated VSMCs actively promote calcification in the medial layer of the arteries by producing a local pro-calcifying environment as well as nidus sites for precipitation of calcium and phosphate and growth of calcium phosphate crystals. Elevated extracellular phosphate induces osteo-/chondrogenic transdifferentiation of VSMCs through complex intracellular signaling pathways, which are still incompletely understood. The present review addresses critical intracellular pathways controlling osteo-/chondrogenic transdifferentiation of VSMCs and, thus, vascular calcification during hyperphosphatemia. Elucidating these pathways holds a significant promise to open novel therapeutic opportunities counteracting the progression of vascular calcification in CKD.
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MESH Headings
- Animals
- Calcium Phosphates/chemistry
- Calcium Phosphates/metabolism
- Cell Transdifferentiation
- Chondrocytes/metabolism
- Chondrocytes/pathology
- Gene Expression Regulation
- Humans
- Hyperphosphatemia/complications
- Hyperphosphatemia/genetics
- Hyperphosphatemia/metabolism
- Hyperphosphatemia/pathology
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- NF-kappa B/genetics
- NF-kappa B/metabolism
- Osteoblasts/metabolism
- Osteoblasts/pathology
- RANK Ligand/genetics
- RANK Ligand/metabolism
- Receptor Activator of Nuclear Factor-kappa B/genetics
- Receptor Activator of Nuclear Factor-kappa B/metabolism
- Renal Insufficiency, Chronic/complications
- Renal Insufficiency, Chronic/genetics
- Renal Insufficiency, Chronic/metabolism
- Renal Insufficiency, Chronic/pathology
- Signal Transduction
- Vascular Calcification/complications
- Vascular Calcification/genetics
- Vascular Calcification/metabolism
- Vascular Calcification/pathology
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Affiliation(s)
- Jakob Voelkl
- Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Altenberger Strasse 69, 4040, Linz, Austria.
- Department of Internal Medicine and Cardiology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburgerplatz 1, 13353, Berlin, Germany.
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 13347, Berlin, Germany.
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Augustenburgerplatz 1, 13353, Berlin, Germany.
| | - Florian Lang
- Department of Physiology I, Eberhard-Karls University, Wilhelmstr. 56, 72076, Tübingen, Germany
| | - Kai-Uwe Eckardt
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Augustenburgerplatz 1, 13353, Berlin, Germany
| | - Kerstin Amann
- Department of Nephropathology, Universität Erlangen-Nürnberg, Krankenhausstr. 8-10, 91054, Erlangen, Germany
| | - Makoto Kuro-O
- Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Andreas Pasch
- Calciscon AG, Aarbergstrasse 5, 2560, Nidau-Biel, Switzerland
| | - Burkert Pieske
- Department of Internal Medicine and Cardiology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburgerplatz 1, 13353, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 13347, Berlin, Germany
- Berlin Institute of Health (BIH), Anna-Louisa-Karsch Str. 2, 10178, Berlin, Germany
- Department of Internal Medicine and Cardiology, German Heart Center Berlin (DHZB), Augustenburger Platz 1, 13353, Berlin, Germany
| | - Ioana Alesutan
- Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Altenberger Strasse 69, 4040, Linz, Austria
- Department of Internal Medicine and Cardiology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburgerplatz 1, 13353, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 13347, Berlin, Germany
- Berlin Institute of Health (BIH), Anna-Louisa-Karsch Str. 2, 10178, Berlin, Germany
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Rodelo-Haad C, Santamaria R, Muñoz-Castañeda JR, Pendón-Ruiz de Mier MV, Martin-Malo A, Rodriguez M. FGF23, Biomarker or Target? Toxins (Basel) 2019; 11:E175. [PMID: 30909513 PMCID: PMC6468608 DOI: 10.3390/toxins11030175] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 03/14/2019] [Accepted: 03/19/2019] [Indexed: 12/11/2022] Open
Abstract
Fibroblast growth factor 23 (FGF23) plays a key role in the complex network between the bones and other organs. Initially, it was thought that FGF23 exclusively regulated phosphate and vitamin D metabolism; however, recent research has demonstrated that an excess of FGF23 has other effects that may be detrimental in some cases. The understanding of the signaling pathways through which FGF23 acts in different organs is crucial to develop strategies aiming to prevent the negative effects associated with high FGF23 levels. FGF23 has been described to have effects on the heart, promoting left ventricular hypertrophy (LVH); the liver, leading to production of inflammatory cytokines; the bones, inhibiting mineralization; and the bone marrow, by reducing the production of erythropoietin (EPO). The identification of FGF23 receptors will play a remarkable role in future research since its selective blockade might reduce the adverse effects of FGF23. Patients with chronic kidney disease (CKD) have very high levels of FGF23 and may be the population suffering from the most adverse FGF23-related effects. The general population, as well as kidney transplant recipients, may also be affected by high FGF23. Whether the association between FGF23 and clinical events is causal or casual remains controversial. The hypothesis that FGF23 could be considered a therapeutic target is gaining relevance and may become a promising field of investigation in the future.
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Affiliation(s)
- Cristian Rodelo-Haad
- Nephrology Service, University Hospital Reina Sofia, 14005 Cordoba, Spain.
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC)/University of Cordoba, 14005 Cordoba, Spain.
- Spanish Renal Research Network (REDinREN), Institute of Health Carlos III, 28040 Madrid, Spain.
| | - Rafael Santamaria
- Nephrology Service, University Hospital Reina Sofia, 14005 Cordoba, Spain.
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC)/University of Cordoba, 14005 Cordoba, Spain.
- Spanish Renal Research Network (REDinREN), Institute of Health Carlos III, 28040 Madrid, Spain.
| | - Juan R Muñoz-Castañeda
- Nephrology Service, University Hospital Reina Sofia, 14005 Cordoba, Spain.
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC)/University of Cordoba, 14005 Cordoba, Spain.
- Spanish Renal Research Network (REDinREN), Institute of Health Carlos III, 28040 Madrid, Spain.
| | - M Victoria Pendón-Ruiz de Mier
- Nephrology Service, University Hospital Reina Sofia, 14005 Cordoba, Spain.
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC)/University of Cordoba, 14005 Cordoba, Spain.
- Spanish Renal Research Network (REDinREN), Institute of Health Carlos III, 28040 Madrid, Spain.
| | - Alejandro Martin-Malo
- Nephrology Service, University Hospital Reina Sofia, 14005 Cordoba, Spain.
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC)/University of Cordoba, 14005 Cordoba, Spain.
- Spanish Renal Research Network (REDinREN), Institute of Health Carlos III, 28040 Madrid, Spain.
| | - Mariano Rodriguez
- Nephrology Service, University Hospital Reina Sofia, 14005 Cordoba, Spain.
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC)/University of Cordoba, 14005 Cordoba, Spain.
- Spanish Renal Research Network (REDinREN), Institute of Health Carlos III, 28040 Madrid, Spain.
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Aging, metabolic acidosis and renal failure: Interactive accelerating processes. Med Hypotheses 2019; 124:95-97. [DOI: 10.1016/j.mehy.2019.02.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 01/03/2019] [Accepted: 02/02/2019] [Indexed: 11/22/2022]
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