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Christoffersen BØ, Kristensen CA, Lindgaard R, Kirk RK, Viuff BM, Kvist PH, Pedersen HD, Ludvigsen TP, Skovgaard T, Fels JJ, Martinussen T, Christiansen LB, Cirera S, Olsen LH. Functional and morphological renal changes in a Göttingen Minipig model of obesity-related and diabetic nephropathy. Sci Rep 2023; 13:6017. [PMID: 37045950 PMCID: PMC10097698 DOI: 10.1038/s41598-023-32674-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 03/31/2023] [Indexed: 04/14/2023] Open
Abstract
Obesity-related glomerulopathy and diabetic nephropathy (DN) are serious complications to metabolic syndrome and diabetes. The purpose was to study effects of a fat, fructose and cholesterol-rich (FFC) diet with and without salt in order to induce hypertension on kidney function and morphology in Göttingen Minipigs with and without diabetes. Male Göttingen Minipigs were divided into 4 groups: SD (standard diet, n = 8), FFC (FFC diet, n = 16), FFC-DIA (FFC diet + diabetes, n = 14), FFC-DIA + S (FFC diet with extra salt + diabetes, n = 14). Blood and urine biomarkers, glomerular filtration rate (GFR), blood pressure (BP) and resistive index (RI) were evaluated after 6-7 months (T1) and 12-13 months (T2). Histology, electron microscopy and gene expression (excluding FFC-DIA + S) were evaluated at T2. All groups fed FFC-diet displayed obesity, increased GFR and RI, glomerulomegaly, mesangial expansion (ME) and glomerular basement membrane (GBM) thickening. Diabetes on top of FFC diet led to increased plasma glucose and urea and proteinuria and tended to exacerbate the glomerulomegaly, ME and GBM thickening. Four genes (CDKN1A, NPHS2, ACE, SLC2A1) were significantly deregulated in FFC and/or FFC-DIA compared to SD. No effects on BP were observed. Göttingen Minipigs fed FFC diet displayed some of the renal early changes seen in human obesity. Presence of diabetes on top of FFC diet exacerbated the findings and lead to changes resembling the early phases of human DN.
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Affiliation(s)
| | - Camilla Aarup Kristensen
- Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark
- AJ Vaccines A/S, Copenhagen S, Denmark
| | - Rikke Lindgaard
- Novo Nordisk A/S, Måløv, Denmark
- Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark
- AniCura ApS, Herlev, Denmark
| | | | | | | | | | | | - Tine Skovgaard
- Novo Nordisk A/S, Måløv, Denmark
- Unilabs, Copenhagen, Denmark
| | | | - Torben Martinussen
- Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Liselotte Bruun Christiansen
- Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark
- Novo Nordisk A/S, Søborg, Denmark
| | - Susanna Cirera
- Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Lisbeth Høier Olsen
- Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark.
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Wu CC, Liao MT, Hsiao PJ, Lu CL, Hsu YJ, Lu KC, Chu P. Antiproteinuria Effect of Calcitriol in Patients With Chronic Kidney Disease and Vitamin D Deficiency: A Randomized Controlled Study. J Ren Nutr 2019; 30:200-207. [PMID: 31704188 DOI: 10.1053/j.jrn.2019.09.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Revised: 07/27/2019] [Accepted: 09/01/2019] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE Vitamin D has been demonstrated to lessen proteinuria severity in chronic kidney disease (CKD). Compared with healthy populations, patients with CKD may have lower serum levels of 1,25-dihydroxy vitamin D (1,25-(OH)2 D) and 25-hydroxy vitamin D (25-(OH) D). We investigated the effect of oral low-dose active vitamin D (calcitriol at 0.25 μg, 3 times weekly) on urinary protein excretion. DESIGN AND METHODS We conducted a nonblinded and non-placebo-controlled study. In total, 60 patients with CKD (average estimated glomerular filtration rate of >15 mL/min) who received a stable dose of angiotensin receptor blocker (ARB) or angiotensin-converting enzyme inhibitor (ACEI) were enrolled in this 24-week study. We randomly assigned these patients to the vitamin D group (oral calcitriol at 0.25 μg 3 times weekly with an ACEI or ARB) or the control group (ACEI or ARB). Change in the urine protein/creatinine ratio (uPCR) was the primary endpoint in this study. RESULTS The mean baseline uPCRs of the 2 groups were comparable (1.84 ± 0.83 g/g vs. 2.02 ± 0.97 g/g, control vs. vitamin D group; P = .46). After the 24-week treatment, the uPCRs were significantly lower than the baseline values in the vitamin D group (1.35 ± 0.64 g/g; P < .05) but not in the control group. The values of uPCR decreased significantly at 8, 16, and 24 weeks (P < .05 vs. baseline) in the vitamin D group. The values of uPCRs were significantly lower in the vitamin D group than in the control group at 8, 16, and 24 weeks (P < .05). A positive correlation was discovered between reduction in uPCRs at 24-week and baseline 25-(OH) D serum level in the vitamin D group (r = 0.738, P < .001). CONCLUSION Supplementary low-dose active vitamin D could reduce proteinuria in CKD patients with low serum 25-(OH) D levels.
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Affiliation(s)
- Chia-Chao Wu
- Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Min-Tser Liao
- Department of Pediatrics, Taoyuan Armed Forces General Hospital, Taoyuan City, Taiwan; Division of Pediatrics, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Po-Jen Hsiao
- Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Division of Nephrology, Department of Medicine, Fu-Jen Catholic University Hospital, School of Medicine, Fu-Jen Catholic University, New Taipei City 242, Taiwan; Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan City, Taiwan; Department of Life Sciences, National Central University, Taoyuan City, Taiwan
| | - Chien-Lin Lu
- Division of Nephrology, Department of Medicine, Fu-Jen Catholic University Hospital, School of Medicine, Fu-Jen Catholic University, New Taipei City 242, Taiwan
| | - Yu-Juei Hsu
- Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Kuo-Cheng Lu
- Division of Nephrology, Department of Medicine, Fu-Jen Catholic University Hospital, School of Medicine, Fu-Jen Catholic University, New Taipei City 242, Taiwan
| | - Pauling Chu
- Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
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CHOI SW, KWEON SS, LEE YH, RYU SY, CHOI JS, NAM HS, PARK KS, KIM SA, SHIN MH. Parathyroid Hormone Levels Are Independently Associated with eGFR and Albuminuria: The Dong-gu Study. J Nutr Sci Vitaminol (Tokyo) 2018; 64:18-25. [DOI: 10.3177/jnsv.64.18] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- Seong-Woo CHOI
- Department of Preventive Medicine, Chosun University Medical School
| | - Sun-Seog KWEON
- Department of Preventive Medicine, Chonnam National University Medical School
- Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital
| | - Young-Hoon LEE
- Department of Preventive Medicine & Institute of Wonkwang Medical Science, Wonkwang University School of Medicine
| | - So-Yeon RYU
- Department of Preventive Medicine, Chosun University Medical School
| | - Jin-Su CHOI
- Department of Preventive Medicine, Chonnam National University Medical School
| | - Hae-Sung NAM
- Department of Preventive Medicine, Chungnam National University Medical School
| | - Kyeong-Soo PARK
- Department of Preventive Medicine, Seonam University College of Medicine
| | - Sun A KIM
- Department of Preventive Medicine, Chonnam National University Medical School
| | - Min-Ho SHIN
- Department of Preventive Medicine, Chonnam National University Medical School
- Center for Creative Biomedical Scientists, Chonnam National University
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Trovato FM, Catalano D, Ragusa A, Martines GF, Pirri C, Buccheri MA, Di Nora C, Trovato GM. Relationship of MTHFR gene polymorphisms with renal and cardiac disease. World J Nephrol 2015; 4:127-137. [PMID: 25664255 PMCID: PMC4317623 DOI: 10.5527/wjn.v4.i1.127] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2014] [Revised: 11/07/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of different methylenetetrahydrofolate reductase (MTHFR) 677C>T gene polymorphism and hyperhomocysteinemia for the development of renal failure and cardiovascular events, which are controversial.
METHODS: We challenged the relationship, if any, of MTHFR 677C>T and MTHFR 1298A>C polymorphisms with renal and heart function. The present article is a reappraisal of these concepts, investigating within a larger population, and including a subgroup of dialysis patients, if the two most common MTHFR polymorphisms, C677T and A1298C, as homozygous, heterozygous or with a compound heterozygous state, show different association with chronic renal failure requiring hemodialysis. MTHFR polymorphism could be a favorable evolutionary factor, i.e., a protective factor for many ominous conditions, like cancer and renal failure. A similar finding was reported in fatty liver disease in which it is suggested that MTHFR polymorphisms could have maintained and maintain their persistence by an heterozygosis advantage mechanism. We studied a total of 630 Italian Caucasian subject aged 54.60 ± 16.35 years, addressing to the increased hazard of hemodialysis, if any, according to the studied MTHFR genetic polymorphisms.
RESULTS: A favorable association with normal renal function of MTHFR polymorphisms, and notably of MTHFR C677T is present independently of the negative effects of left ventricular hypertrophy, increased Intra-Renal arterial Resistance and hyperparathyroidism.
CONCLUSION: MTHFR gene polymorphisms could have a protective role on renal function as suggested by their lower frequency among our dialysis patients in end-stage renal failure; differently, the association with left ventricular hypertrophy and reduced left ventricular relaxation suggest some type of indirect, or concurrent mechanism.
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Trovato FM, Catalano D, Garozzo A, Martines GF, Pirri C, Trovato GM. ADV36 adipogenic adenovirus in human liver disease. World J Gastroenterol 2014; 20:14706-14716. [PMID: 25356033 PMCID: PMC4209536 DOI: 10.3748/wjg.v20.i40.14706] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 04/03/2014] [Accepted: 06/26/2014] [Indexed: 02/07/2023] Open
Abstract
Obesity and liver steatosis are usually described as related diseases. Obesity is regarded as exclusive consequence of an imbalance between food intake and physical exercise, modulated by endocrine and genetic factors. Non-alcoholic fatty liver disease (NAFLD), is a condition whose natural history is related to, but not completely explained by over-nutrition, obesity and insulin resistance. There is evidence that environmental infections, and notably adipogenic adenoviruses (ADV) infections in humans, are associated not only with obesity, which is sufficiently established, but also with allied conditions, such as fatty liver. In order to elucidate the role, if any, of previous ADV36 infection in humans, we investigated association of ADV36-ADV37 seropositivity with obesity and fatty liver in humans. Moreover, the possibility that lifestyle-nutritional intervention in patients with NAFLD and different ADV36 seropositive status, achieves different clinical outcomes on ultrasound bright liver imaging, insulin resistance and obesity was challenged. ADV36 seropositive patients have a more consistent decrease in insulin resistance, fatty liver severity and body weight in comparison with ADV36 seronegative patients, indicating a greater responsiveness to nutritional intervention. These effects were not dependent on a greater pre-interventional body weight and older age. These results imply that no obvious disadvantage - and, seemingly, that some benefit - is linked to ADV36 seropositivity, at least in NAFLD. ADV36 previous infection can boost weight loss and recovery of insulin sensitivity under interventional treatment.
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Trovato GM, Catalano D, Ragusa A, Martines GF, Tonzuso A, Pirri C, Buccheri MA, Di Nora C, Trovato FM. Renal insufficiency in non-diabetic subjects: relationship of MTHFR C677t gene polymorphism and left ventricular hypertrophy. Ren Fail 2013; 35:615-23. [PMID: 23534584 DOI: 10.3109/0886022x.2013.779895] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Association of methylenetetrahydrofolate reductase (MTHFR) 677C>T gene polymorphism with hyperhomocysteinemia, renal failure, and cardiovascular events is controversial. We investigated the relationship of MTHFR 677C>T polymorphisms with left ventricular hypertrophy (LVH) and renal insufficiency. METHODS Glomerular filtration rate (GFR) and left myocardial ventricular mass/m2 were assessed in 138 non-diabetic subjects (age, 50.93 ± 14.85 years; body mass index, 27.95 ± 5.98 kg/m(2)), 38 no-mutation wild MTHFR C677CC, 52 heterozygous MTHFR C677CT, and 48 homozygous MTHFR C677TT, all with adequate adherence to current international healthy dietary guidelines. Serum homocysteine, insulin resistance, high-sensitivity C-reactive-protein (hsCRP), parathyroid hormone, and renal artery resistive index (RRI) were challenged by odds ratio analysis and multiple linear regression models. RESULTS MTHFR 677C>T polymorphism showed higher GFR (73.8 ± 27.99 vs. 58.64 ± 29.95; p= 0.001) and lower renal failure odds (OR, 0.443; 95% confidence interval, 0.141-1.387) in comparison with wild MTHFR genotype. A favorable effect on GFR of MTHFR polymorphism is presented independently by the negative effects of LVH, increased intra-renal arterial resistance, and hyperparathyroidism; GFR is the significant predictive factor to LVH. CONCLUSIONS Renal insufficiency in non-diabetic subjects is explained by interactions of MTHFR C677T polymorphism mutation with LVH, hsCRP, intact parathyroid hormone (iPTH), and RRI. Sign of these predictive effects is opposite: subjects with MTHFR 677C>T polymorphism have lower likelihood of renal insufficiency; differently, wild-type MTHFR genotype subjects have lower GFR and greater hsCRP, iPTH, RRI, and LVH.
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