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Gembillo G, Spadaro G, Santoro D. Link between obstructive uropathy and acute kidney injury. World J Nephrol 2025; 14:99120. [DOI: 10.5527/wjn.v14.i1.99120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 10/10/2024] [Accepted: 11/19/2024] [Indexed: 01/20/2025] Open
Abstract
Obstructive uropathy represents a major risk of acute kidney injury. From an epidemiological point of view, it is responsible for 5% to 10% of cases of acute renal failure and 4% of cases of end-stage kidney disease. Although obstructive uropathy is a recognized disease, there is a significant lack of detailed research on this topic from both a nephrological and urological perspective. The majority of published research focuses on the pathophysiology of the topic and neglects a comprehensive analysis of diagnostic and treatment approaches supported by current data. In this context, it is crucial to assess the overall hemodynamic status, especially in the presence of urosepsis. Once clinical stability is assured, it is important to focus on symptom management, usually by controlling pain. Ultimately, it is crucial to decide immediately whether the patient should receive a prompt urinary diversion. Urinary diversion is an essential part of the treatment of obstructive uropathy and should be initiated promptly and without unnecessary delay once the diagnosis has been confirmed. Functional recovery of the obstructed kidney after decompression of the urinary tract depends on the degree of obstruction, the duration of the obstruction and the presence of a concomitant urinary tract infection. The timing and proper treatment of this condition determines the recovery of kidney function after an obstruction and prevents the development of chronic kidney disease. In this editorial, we emphasized the pathophysiological role and clinical significance of obstructive uropathy in the context of acute kidney injury.
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Affiliation(s)
- Guido Gembillo
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina 98125, Italy
| | - Giuseppe Spadaro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina 98125, Italy
| | - Domenico Santoro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina 98125, Italy
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Fogo AB, Harris RC. Crosstalk between glomeruli and tubules. Nat Rev Nephrol 2025; 21:189-199. [PMID: 39643696 DOI: 10.1038/s41581-024-00907-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2024] [Indexed: 12/09/2024]
Abstract
Models of kidney injury have classically concentrated on glomeruli as the primary site of injury leading to glomerulosclerosis or on tubules as the primary site of injury leading to tubulointerstitial fibrosis. However, current evidence on the mechanisms of progression of chronic kidney disease indicates that a complex interplay between glomeruli and tubules underlies progressive kidney injury. Primary glomerular injury can clearly lead to subsequent tubule injury. For example, damage to the glomerular filtration barrier can expose tubular cells to serum proteins, including complement and cytokines, that would not be present in physiological conditions and can promote the development of tubulointerstitial fibrosis and progressive decline in kidney function. In addition, although less well-studied, increasing evidence suggests that tubule injury, whether primary or secondary, can also promote glomerular damage. This feedback from the tubule to the glomerulus might be mediated by changes in the reabsorptive capacity of the tubule, which can affect the glomerular filtration rate, or by mediators released by injured proximal tubular cells that can induce damage in both podocytes and parietal epithelial cells. Examining the crosstalk between the various compartments of the kidney is important for understanding the mechanisms underlying kidney pathology and identifying potential therapeutic interventions.
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Affiliation(s)
- Agnes B Fogo
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Raymond C Harris
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
- Tennessee Department of Veterans Affairs, Nashville, TN, USA.
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Elgendy AM, Nafie MS, Nabil ZI, El-Shenawy NS, Gad El-Hak HN. Unveiling the antiurolithiatic potentiality of two benzene sulfonamide derivatives against ethylene glycol-induced renal calculi. Nefrologia 2025; 45:167-181. [PMID: 39986714 DOI: 10.1016/j.nefroe.2025.02.003] [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: 08/07/2024] [Accepted: 09/24/2024] [Indexed: 02/24/2025] Open
Abstract
OBJECTIVE Oxidative stress and inflammation play crucial roles in the onset of kidney injury and crystal formation caused by hyperoxaluria. Indapamide is a potent medication for treating renal calculi, but it has severe side effects such as hypokalemia, hypercalcemia, and hyperuricemia. Therefore, it is advisable to explore alternative treatments that do not have these side effects. The study aimed to reveal the antiurolithiatic potential of two benzene sulfonamide derivatives (SBCl and SBF; A and B, respectively) against ethylene glycol-induced kidney stones. METHODS The rats were divided into two main groups: the first group consisted of 20 rats with induced kidney stones, and the second group included 15 control rats. This division enabled a comparative analysis between rats with kidney stones and those without, offering insights into the effects of kidney stone induction on various physiological parameters and biochemical markers. The effectiveness of benzene sulfonamide derivatives (compounds A and B) was assessed in rats with induced kidney stones. The treatment was given orally by gavage for 21 days, administered every 48h after inducing kidney stones with 0.12ml of 5% ethylene glycol (EG). RESULTS The influence of compounds A and B on electrolytes, biochemical, antioxidant, and inflammatory reactions in induced kidneys underscores their potential therapeutic advantages in alleviating the advancement of kidney stone disease and related complications. CONCLUSION Both compounds were found to possess equal effectiveness in inhibiting the complications of stone formation. However, SBCl-EG showed superior antioxidant and inflammatory parameters effects compared to SBF-EG. Our study's findings underscore the potential benefits of derivatives in treating nephrolithiasis and related oxidative disorders, highlighting their superior effects on antioxidant and inflammatory responses compared to standard treatments.
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Affiliation(s)
- Ahmed M Elgendy
- Zoology Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
| | - Mohamed S Nafie
- Department of Chemistry, College of Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates (UAE); Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
| | - Zohour I Nabil
- Zoology Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
| | - Nahla S El-Shenawy
- Zoology Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt.
| | - Heba N Gad El-Hak
- Zoology Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
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Khater Y, Barakat N, Shokeir A, Hamed M, Samy A, Karrouf G. Synergy of zinc oxide nanoparticles to losartan attenuates kidney injury induced by unilateral ureteral obstruction through modulation of the TNF-α/IL6 and BAX/BCL2 signaling pathways. Int Urol Nephrol 2025:10.1007/s11255-024-04331-y. [PMID: 39810058 DOI: 10.1007/s11255-024-04331-y] [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: 11/29/2024] [Accepted: 12/17/2024] [Indexed: 01/16/2025]
Abstract
AIM Although the relief of ureteral obstruction seems to be a radical treatment for obstructive uropathy (OU), progressive kidney damage is the result because of the associated increased apoptosis and fibrosis. Therefore, it is urgent to find a complementary renoprotective therapy against partially obstructed uropathy cascades. Thus, this study investigated the renoprotective effects of both losartan (LOS) and zinc oxide nanoparticles (ZnONPs) in partial unilateral ureteral obstruction (PUUO). MAIN METHODS In controlled (n = 16) and shamed (n = 16) study, 64 healthy male Sprague-Dawley rats, both PUUO and right nephrectomy (RNX) were induced. The rats were equally allocated into four groups according to treatment protocol: (1) PUUO group (no treatment), (2) ZnONPs group, (3) LOS group and (4) ZnONPs/LOS group. Antioxidant status and gene expression were assessed in renal tissues. Moreover, histologic and immunohistochemical examinations were performed. KEY FINDINGS LOS and ZnONPs significantly mitigated the PUUO-induced renal injury, by significant (P < 0.0001) suppressing of oxidative stress (MDA and TOS), upregulating of antioxidant gene (SOD) and antiapoptotic gene (BCL2), and downregulating the expression of inflammatory cytokines (TNF-α, and IL6), apoptotic gene (Bax) and fibrotic marker (β-Catenin). The combination of both agents offered a more powerful renoprotective effect with additional significant upregulation of the antioxidant marker (TAC, P < 0.0001). SIGNIFICANCE Both losartan and ZnONPs and specially their combination have synergistic action in protecting the kidney against PUUO-induced chronic renal cascades through improvement the renal function tests, amelioration of oxidative stress, inhibition of induced apoptosis and fibrosis with marked renal regeneration which highlights the possible application of these drugs as a complementary therapies for different chronic renal degenerative diseases.
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Affiliation(s)
- Yomna Khater
- Medical Experimental Research Centre, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt
| | - Nashwa Barakat
- Urology and Nephrology Center, Mansoura University, Mansoura, 35516, Egypt
| | - Ahmed Shokeir
- Urology and Nephrology Center, Mansoura University, Mansoura, 35516, Egypt
- Centre of Excellence of Genome and Cancer Research, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt
| | - Mohamed Hamed
- Department of Pathology, Faculty of Veterinary Medicine, University of Mansoura, Mansoura, 35516, Egypt
| | - Alaa Samy
- Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, University of Mansoura, Mansoura, 35516, Egypt
| | - Gamal Karrouf
- Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, University of Mansoura, Mansoura, 35516, Egypt.
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Yang AY, Kim JY, Gwon MG, Kwon HH, Leem J, Jeon EJ. Protective Effects of Tormentic Acid on Unilateral Ureteral Obstruction-Induced Renal Injury, Inflammation, and Fibrosis: A Comprehensive Approach to Reducing Oxidative Stress, Apoptosis, and Ferroptosis. Antioxidants (Basel) 2024; 14:13. [PMID: 39857346 PMCID: PMC11762340 DOI: 10.3390/antiox14010013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 12/18/2024] [Accepted: 12/21/2024] [Indexed: 01/27/2025] Open
Abstract
Chronic kidney disease (CKD) progresses through mechanisms involving inflammation, fibrosis, and oxidative stress, leading to the gradual structural and functional deterioration of the kidneys. Tormentic acid (TA), a triterpenoid compound with known anti-inflammatory and antioxidant properties, shows significant potential in counteracting these pathological processes. This study explored the protective role of TA in a unilateral ureteral obstruction (UUO)-induced CKD model. Mice received TA through intraperitoneal injections at a dosage of 5 mg/kg per day for 8 consecutive days, commencing a day before the UUO procedure. The TA treatment significantly improved both structural and functional kidney injury. It suppressed cytokine expression and reduced immune cell infiltration, inhibited the activation of the mitogen-activated protein kinase cascade, and alleviated endoplasmic reticulum stress. Moreover, TA displayed potent anti-fibrotic effects by reversing epithelial-to-mesenchymal transition and inhibiting Smad2/3 activation, reducing extracellular matrix deposition. TA also mitigated oxidative stress by attenuating lipid peroxidation and boosting antioxidant defenses. Additionally, it inhibited apoptosis and ferroptosis by reducing oxidative stress and modulating key cell death markers. Collectively, these findings indicate that TA provides comprehensive renoprotection in the UUO model by effectively targeting inflammation, fibrosis, oxidative stress, and tubular cell death in CKD progression.
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Affiliation(s)
- Ah Young Yang
- Department of Immunology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea; (A.Y.Y.); (J.-Y.K.); (M.-G.G.)
| | - Jung-Yeon Kim
- Department of Immunology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea; (A.Y.Y.); (J.-Y.K.); (M.-G.G.)
| | - Mi-Gyeong Gwon
- Department of Immunology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea; (A.Y.Y.); (J.-Y.K.); (M.-G.G.)
| | - Hyun Hee Kwon
- Department of Internal Medicine, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea;
| | - Jaechan Leem
- Department of Immunology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea; (A.Y.Y.); (J.-Y.K.); (M.-G.G.)
| | - Eon-Ju Jeon
- Department of Internal Medicine, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea;
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Zhang YY, Zhou XT, Huang GZ, Liao WJ, Chen X, Ma YR. The pro-fibrotic role of autophagy in renal intrinsic cells: mechanisms and therapeutic potential in chronic kidney disease. Front Cell Dev Biol 2024; 12:1499457. [PMID: 39723243 PMCID: PMC11669005 DOI: 10.3389/fcell.2024.1499457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 11/25/2024] [Indexed: 12/28/2024] Open
Abstract
Chronic kidney disease (CKD) represents a significant global public health burden, affecting over 10% of the world's population. Its high morbidity, multifactorial complications, and substantial mortality impose significant burdens on healthcare systems and patients, necessitating considerable investment in healthcare resources. Renal fibrosis (RF) is a key pathological feature and driver of CKD progression. Extensive research indicates that autophagy participates in the complete pathogenesis of RF. Under physiological conditions, autophagy is essential for maintaining renal cellular homeostasis. However, under pathological conditions, perhaps aberrant and sustained activation of autophagy contributes to oxidative stress, apoptosis, inflammation, etc. Ultimately, they accelerate the development of RF. The role of autophagy in RF is currently controversial. This review investigates the molecular mechanisms by which intrinsic renal cell autophagy contributes to RF across diverse disease models, suggesting that autophagy and its associated regulatory pathways represent potential diagnostic and therapeutic targets for CKD.
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Affiliation(s)
- Ying-Ying Zhang
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xiao-Tao Zhou
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Geng-Zhen Huang
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Chengdu second people’s Hospital, Chengdu, China
| | - Wen-Jun Liao
- The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xian Chen
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yue-Rong Ma
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Cohen EP, Denic A, Aperna F, Mullan AF, Barisoni L, Sharma V, Gibson IW, Rule AD. Stenosis of the glomerulotubular neck in progressive chronic kidney disease. Nephrol Dial Transplant 2024:gfae234. [PMID: 39415419 DOI: 10.1093/ndt/gfae234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2024] Open
Abstract
BACKGROUND Morphology and morphometric evaluation of lesions beyond conventional parameters can inform the pathophysiology of chronic kidney disease (CKD). We sought to determine whether the occurrence of glomerulotubular neck stenoses associates with progressive CKD. METHODS We evaluated the normal parenchyma from radical nephrectomies removed for tumor between 2000 and 2021 and analyzed cortex for stenoses of the glomerulotubular neck. Stenosis of the glomerulotubular neck is defined a focal narrowing for which the draining tubule has a greater diameter than at the neck. Progressive CKD was defined as dialysis, kidney transplantation, sustained eGFR <10 ml/min per 1.73m2 or sustained 40% decline from the post-nephrectomy eGFR. Each case of progressive CKD was age-sex-matched to 2 controls without progressive CKD. Logistic regression models assessed the risk of progressive CKD with stenotic necks adjusting for other histological features, kidney function, and CKD risk factors. RESULTS There were 65 cases with a mean of 255 glomeruli and 130 controls with a mean of 329 glomeruli. Among both cases and controls, 5% of glomeruli showed visible glomerulotubular necks. The proportion of necks that were stenotic was higher in cases than controls (35% vs. 11%, p<0.0001). Stenotic necks associated with progressive CKD independent of other histologic and clinical characteristics. CONCLUSION Glomerulotubular neck stenosis is associated with development of progressive CKD.
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Affiliation(s)
- Eric P Cohen
- Division of Nephrology, NYU Grossman School of Medicine, New York, NY
| | - Aleksandar Denic
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
| | - Fnu Aperna
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
| | - Aidan F Mullan
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN
| | - Laura Barisoni
- Department of Pathology, Division of AI & Computational Pathology, and Department of Medicine, Division of Nephrology, Duke University, Durham, NC
- Department of Medicine, Division of Nephrology, Duke University, Durham, NC
| | | | - Ian W Gibson
- Department of Pathology, University of Manitoba, Winnipeg, MB, Canada
| | - Andrew D Rule
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
- Division of Epidemiology, Mayo Clinic, Rochester, MN
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Babickova J, Yang HC, Fogo AB. Adverse effects of acute tubular injury on the glomerulus: contributing factors and mechanisms. Pediatr Nephrol 2024; 39:2301-2308. [PMID: 38191938 DOI: 10.1007/s00467-023-06264-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 12/04/2023] [Accepted: 12/14/2023] [Indexed: 01/10/2024]
Abstract
The intricate relationship between tubular injury and glomerular dysfunction in kidney diseases has been a subject of extensive research. While the impact of glomerular injury on downstream tubules has been well-studied, the reverse influence of tubular injury on the glomerulus remains less explored. This paper provides a comprehensive review of recent advances in the field, focusing on key pathways and players implicated in the pathogenesis of tubular injury on glomerular dysfunction. Anatomical and physiological evidence supports the possibility of crosstalk from the tubule to the glomerulus, whereby various mechanisms contribute to glomerular injury following tubular injury. These mechanisms include tubular backleak, dysfunctional tubuloglomerular feedback, capillary rarefaction, atubular glomeruli, and the secretion of factors from damaged tubular epithelial cells. Clinical evidence further supports the association between even mild or recovered acute kidney injury and an increased risk of chronic kidney disease, including glomerular diseases. We also discuss potential therapeutic interventions aimed at mitigating acute tubular injury, thereby reducing the detrimental effects on glomerular function. By unraveling the complex interplay from tubular injury to glomerular dysfunction, we aim to provide insights that can enhance clinical management strategies and improve outcomes for patients with kidney disease.
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Affiliation(s)
- Janka Babickova
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, MCN C3318, Nashville, TN, 37232, USA
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Hai-Chun Yang
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, MCN C3318, Nashville, TN, 37232, USA
| | - Agnes B Fogo
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, MCN C3318, Nashville, TN, 37232, USA.
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Nakashima M, Suga N, Ikeda Y, Yoshikawa S, Matsuda S. Inspiring Tactics with the Improvement of Mitophagy and Redox Balance for the Development of Innovative Treatment against Polycystic Kidney Disease. Biomolecules 2024; 14:207. [PMID: 38397444 PMCID: PMC10886467 DOI: 10.3390/biom14020207] [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: 12/21/2023] [Revised: 01/31/2024] [Accepted: 02/08/2024] [Indexed: 02/25/2024] Open
Abstract
Polycystic kidney disease (PKD) is the most common genetic form of chronic kidney disease (CKD), and it involves the development of multiple kidney cysts. Not enough medical breakthroughs have been made against PKD, a condition which features regional hypoxia and activation of the hypoxia-inducible factor (HIF) pathway. The following pathology of CKD can severely instigate kidney damage and/or renal failure. Significant evidence verifies an imperative role for mitophagy in normal kidney physiology and the pathology of CKD and/or PKD. Mitophagy serves as important component of mitochondrial quality control by removing impaired/dysfunctional mitochondria from the cell to warrant redox homeostasis and sustain cell viability. Interestingly, treatment with the peroxisome proliferator-activated receptor-α (PPAR-α) agonist could reduce the pathology of PDK and might improve the renal function of the disease via the modulation of mitophagy, as well as the condition of gut microbiome. Suitable modulation of mitophagy might be a favorable tactic for the prevention and/or treatment of kidney diseases such as PKD and CKD.
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Affiliation(s)
| | | | | | | | - Satoru Matsuda
- Department of Food Science and Nutrition, Nara Women’s University, Kita-Uoya Nishimachi, Nara 630-8506, Japan
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CHAPMAN ARLENE, CHEN PEILI. ALTERATIONS IN HISTIDINE METABOLISM IS A FEATURE OF EARLY AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD). TRANSACTIONS OF THE AMERICAN CLINICAL AND CLIMATOLOGICAL ASSOCIATION 2024; 134:47-65. [PMID: 39135565 PMCID: PMC11316905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 08/15/2024]
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by epithelial proliferation and progressive cyst enlargement. Using a non-targeted high-resolution metabolomics approach, we analyzed biofluids from 36 ADPKD and 18 healthy controls with estimated glomerular filtration rate (eGFR) > 60 ml/min to identify features specific to ADPKD or that associate with disease severity [eGFR or height-corrected total kidney volume (htTKV)]. Multiple pathways differed between ADPKD subjects and controls, with the histidine pathway being the most highly represented. Plasma histidine, urinary N-methylhistamine, methylimidazole-acetaldehyde, and imidazole-acetaldehyde, as well as 3-methylhistidine and anserine were increased, while plasma N-acetylhistamine and urinary imidazole-acetic acid were decreased in ADPKD compared to controls. In ADPKD, urinary histidine and a histidine derivative, urocanate (a precursor of glutamate), were significantly associated. HtTKV and eGFR were inversely associated with urinary glutamine and plasma 4-imidazolone-5-propionic acid, respectively. Supernatant from cultured human ADPKD renal cystic epithelia demonstrated increased aspartate and glutamate levels at 8 and 24 hours compared to primary tubular epithelia (p < 0.001). Following exposure over 48 hours to α-fluromethylhistidine, an inhibitor of histamine production, primary human PKD1 cyst epithelia proliferation increased significantly from baseline (p < 0.01) and greater than non-cystic epithelia (p < 0.05). The histidine ammonia lyase inhibitor nitromethane reversed α-fluromethylhistidine-induced cyst epithelia proliferation indicating a role for glutamate in cyst growth. In conclusion, histidine metabolism is altered preferentially leading to glutamate production and epithelial proliferation in ADPKD and associates with disease severity.
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Nørregaard R, Mutsaers HAM, Frøkiær J, Kwon TH. Obstructive nephropathy and molecular pathophysiology of renal interstitial fibrosis. Physiol Rev 2023; 103:2827-2872. [PMID: 37440209 PMCID: PMC10642920 DOI: 10.1152/physrev.00027.2022] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 07/05/2023] [Accepted: 07/09/2023] [Indexed: 07/14/2023] Open
Abstract
The kidneys play a key role in maintaining total body homeostasis. The complexity of this task is reflected in the unique architecture of the organ. Ureteral obstruction greatly affects renal physiology by altering hemodynamics, changing glomerular filtration and renal metabolism, and inducing architectural malformations of the kidney parenchyma, most importantly renal fibrosis. Persisting pathological changes lead to chronic kidney disease, which currently affects ∼10% of the global population and is one of the major causes of death worldwide. Studies on the consequences of ureteral obstruction date back to the 1800s. Even today, experimental unilateral ureteral obstruction (UUO) remains the standard model for tubulointerstitial fibrosis. However, the model has certain limitations when it comes to studying tubular injury and repair, as well as a limited potential for human translation. Nevertheless, ureteral obstruction has provided the scientific community with a wealth of knowledge on renal (patho)physiology. With the introduction of advanced omics techniques, the classical UUO model has remained relevant to this day and has been instrumental in understanding renal fibrosis at the molecular, genomic, and cellular levels. This review details key concepts and recent advances in the understanding of obstructive nephropathy, highlighting the pathophysiological hallmarks responsible for the functional and architectural changes induced by ureteral obstruction, with a special emphasis on renal fibrosis.
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Affiliation(s)
- Rikke Nørregaard
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | | | - Jørgen Frøkiær
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Tae-Hwan Kwon
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Taegu, Korea
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12
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El Tohamy M, Adel M, Rashad El-Menabawy F, Gad GEM, El-Gamal R, El Serougy H. Role of Cannabinoid Type 2 Receptor Activation in Renal Fibrosis Induced by Unilateral Ureteric Obstruction in Rats. Rep Biochem Mol Biol 2023; 12:59-73. [PMID: 37724148 PMCID: PMC10505471 DOI: 10.52547/rbmb.12.1.59] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 02/01/2023] [Indexed: 09/20/2023]
Abstract
Background Chronic kidney disease (CKD) ends mostly with renal fibrosis. The effect of CB2 receptor on renal fibrosis has been unclear. The aim of this study was to investigate the effect of CB2 receptor on renal fibrosis and the mechanisms behind it. Methods 50 adult male Sprague-Dawley rats were divided into 5 groups; normal, sham; rats had their ureters only manipulated, UUO; rats had their left ureters ligated, and JWH post; rats had their left ureters ligated and they received JWH 133 for 14 days, JWH pre+post; rats received JWH 133 for 14 days before and after UUO procedure. Serum creatinine and BUN were assessed together with tissue MDA, GSH, and catalase. Histopathological evaluation of the renal tissue by H&E and Masson's trichrome was done. Immunohistochemical staining for TGF-β1, AQP1, Caspase-3, LC3B and p62 was performed. AQP1 and CB2 receptors genes expression was detected by quantitative RT-PCR. Results UUO had caused severe damage in the renal tissue with reduction of the renal function parameter accompanied by increase in the collagen deposition with increase TGF-β1 and decrease AQP1 expression. Conclusions The improvement of these parameters with JWH-133 suggests an anti-fibrotic role of CB2 receptor activation through reduction of oxidative stress, apoptosis, and autophagy.
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Affiliation(s)
- Mahmoud El Tohamy
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Egypt.
| | - Mohamed Adel
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Egypt.
| | | | - Gad El Mawla Gad
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Egypt.
| | - Randa El-Gamal
- Department of Biochemistry, Faculty of Medicine, Mansoura University, Egypt.
| | - Hanaa El Serougy
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Egypt.
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Peng Z, Wang H, Zheng J, Wang J, Xiang Y, Liu C, Ji M, Liu H, Pan L, Qin X, Qu X. Is the proximal tubule the focus of tubulointerstitial fibrosis? Heliyon 2023; 9:e13508. [PMID: 36846656 PMCID: PMC9950842 DOI: 10.1016/j.heliyon.2023.e13508] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/15/2023] [Accepted: 02/01/2023] [Indexed: 02/09/2023] Open
Abstract
Tubulointerstitial fibrosis (TIF), a common end result of almost all progressive chronic kidney diseases (CKD), is also the best predictor of kidney survival. Almost all cells in the kidney are involved in the progression of TIF. Myofibroblasts, the primary producers of extracellular matrix, have previously received a great deal of attention; however, a large body of emerging evidence reveals that proximal tubule (PT) plays a central role in TIF progression. In response to injury, renal tubular epithelial cells (TECs) transform into inflammatory and fibroblastic cells, producing various bioactive molecules that drive interstitial inflammation and fibrosis. Here we reviewed the increasing evidence for the key role of the PT in promoting TIF in tubulointerstitial and glomerular injury and discussed the therapeutic targets and carrier systems involving the PT that holds particular promise for treating patients with fibrotic nephropathy.
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Affiliation(s)
- Zhi Peng
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha 410008, Hunan, China
| | - Hui Wang
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha 410008, Hunan, China
| | - Jiaoyun Zheng
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jie Wang
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha 410008, Hunan, China
| | - Yang Xiang
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha 410008, Hunan, China
| | - Chi Liu
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha 410008, Hunan, China
| | - Ming Ji
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha 410008, Hunan, China
| | - Huijun Liu
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha 410008, Hunan, China
| | - Lang Pan
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha 410008, Hunan, China
| | - Xiaoqun Qin
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha 410008, Hunan, China
| | - Xiangping Qu
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha 410008, Hunan, China
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14
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Zhu E, Liu Y, Zhong M, Liu Y, Jiang X, Shu X, Li N, Guan H, Xia Y, Li J, Lan HY, Zheng Z. Targeting NK-1R attenuates renal fibrosis via modulating inflammatory responses and cell fate in chronic kidney disease. Front Immunol 2023; 14:1142240. [PMID: 37033943 PMCID: PMC10080018 DOI: 10.3389/fimmu.2023.1142240] [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: 01/11/2023] [Accepted: 03/13/2023] [Indexed: 04/11/2023] Open
Abstract
Background Renal fibrosis is the final common pathway of chronic kidney disease (CKD), which is clinically irreversible and without effective therapy. Renal tubules are vulnerable to various insults, and tubular injury is involving in the initiation and evolution of renal inflammation and fibrosis. Neurokinin-1 receptor (NK-1R) functions by interacting with proinflammatory neuropeptide substance P (SP), exerting crucial roles in various neurological and non-neurological diseases. However, its roles in renal inflammation and fibrosis are still unknown. Methods We collected renal biopsy specimens and serum samples of individuals with or without CKD. Additionally, knockout mice lacking NK-1R expression, SP addition and NK-1R pharmacological antagonist treatment in the unilateral ureteral obstruction (UUO) model, and NK-1R-overexpressed HK-2 cells were employed. Results Renal SP/NK-1R and serum SP were increased in patients with CKD and mice experiencing UUO and correlated with renal fibrosis and function. SP addition enhanced UUO-induced progressive inflammatory responses and renal fibrosis, whereas genetically or pharmacologically targeting NK-1R attenuated these effects. Mechanistically, TFAP4 promoted NK-1R transcription by binding to its promoter, which was abolished by mutation of the binding site between TFAP4 and NK-1R promoter. Furthermore, SP acted through the NK-1R to activate the JNK/p38 pathways to modulate cell fate of tubular epithelial cells including growth arrest, apoptosis, and expression of profibrogenic genes. Conclusion Our data reveals that SP/NK-1R signaling promotes renal inflammatory responses and fibrosis, suggesting NK-1R could be a potential therapeutic target for the patients with CKD.
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Affiliation(s)
- Enyi Zhu
- Department of Nephrology, Center of Kidney and Urology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Yang Liu
- Department of Nephrology, Center of Kidney and Urology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Ming Zhong
- Department of Nephrology, Center of Kidney and Urology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Yu Liu
- Department of Nephrology, Center of Kidney and Urology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Xi Jiang
- Department of Clinical Laboratory, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Xiaorong Shu
- Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China
| | - Na Li
- Department of Nephrology, Center of Kidney and Urology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Hui Guan
- Department of Nephrology, Center of Kidney and Urology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Yin Xia
- Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Jinhong Li
- Department of Nephrology, Center of Kidney and Urology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
- *Correspondence: Zhihua Zheng, ; Hui-yao Lan, ; Jinhong Li,
| | - Hui-yao Lan
- Departments of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Guangdong-Hong Kong Joint Laboratory for Immune and Genetic Kidney Disease, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China
- *Correspondence: Zhihua Zheng, ; Hui-yao Lan, ; Jinhong Li,
| | - Zhihua Zheng
- Department of Nephrology, Center of Kidney and Urology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
- *Correspondence: Zhihua Zheng, ; Hui-yao Lan, ; Jinhong Li,
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15
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Jin B, Zhu J, Zhou Y, Liang L, Yang Y, Xu L, Zhang T, Li P, Pan T, Guo B, Chen T, Li H. Loss of MEN1 leads to renal fibrosis and decreases HGF-Adamts5 pathway activity via an epigenetic mechanism. Clin Transl Med 2022; 12:e982. [PMID: 35968938 PMCID: PMC9377152 DOI: 10.1002/ctm2.982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 06/28/2022] [Accepted: 07/03/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Renal fibrosis is a serious condition that results in the development of chronic kidney diseases. The MEN1 gene is an epigenetic regulator that encodes the menin protein and its role in kidney tissue remains unclear. METHODS Kidney histology was examined on paraffin sections stained with hematoxylin-eosin staining. Masson's trichrome staining and Sirius red staining were used to analyze renal fibrosis. Gene and protein expression were determined by quantitative real-time PCR (qPCR) and Western blot, respectively. Immunohistochemistry staining in the kidney tissues from mice or patients was used to evaluate protein levels. Flow cytometry was used to analyze the cell cycle distributions and apoptosis. RNA-sequencing was performed for differential expression genes in the kidney tissues of the Men1f/f and Men1∆/∆ mice. Chromatin immunoprecipitation sequencing (ChIP-seq) was carried out for identification of menin- and H3K4me3-enriched regions within the whole genome in the mouse kidney tissue. ChIP-qPCR assays were performed for occupancy of menin and H3K4me3 at the gene promoter regions. Luciferase reporter assay was used to detect the promoter activity. The exacerbated unilateral ureteral obstruction (UUO) models in the Men1f/f and Men1∆/∆ mice were used to assess the pharmacological effects of rh-HGF on renal fibrosis. RESULTS The expression of MEN1 is reduce in kidney tissues of fibrotic mouse and human diabetic patients and treatment with fibrotic factor results in the downregulation of MEN1 expression in renal tubular epithelial cells (RTECs). Disruption of MEN1 in RTECs leads to high expression of α-SMA and Collagen 1, whereas MEN1 overexpression restrains epithelial-to-mesenchymal transition (EMT) induced by TGF-β treatment. Conditional knockout of MEN1 resulted in chronic renal fibrosis and UUO-induced tubulointerstitial fibrosis (TIF), which is associated with an increased induction of EMT, G2/M arrest and JNK signaling. Mechanistically, menin recruits and increases H3K4me3 at the promoter regions of hepatocyte growth factor (HGF) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (Adamts5) genes and enhances their transcriptional activation. In the UUO mice model, exogenous HGF restored the expression of Adamts5 and ameliorated renal fibrosis induced by Men1 deficiency. CONCLUSIONS These findings demonstrate that MEN1 is an essential antifibrotic factor in renal fibrogenesis and could be a potential target for antifibrotic therapy.
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Affiliation(s)
- Bangming Jin
- Department of SurgeryAffiliated Hospital of Guizhou Medical UniversityGuiyangChina
- School of Basic Medical SciencesGuizhou Medical UniversityGuiyangChina
- Transformation Engineering Research Center of Chronic Disease Diagnosis and TreatmentGuizhou Medical UniversityGuiyangChina
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic DiseasesGuizhou Medical UniversityGuiyangChina
- Guizhou Institute of Precision MedicineAffiliated Hospital of Guizhou Medical UniversityGuiyangChina
| | - Jiamei Zhu
- School of Basic Medical SciencesGuizhou Medical UniversityGuiyangChina
- Transformation Engineering Research Center of Chronic Disease Diagnosis and TreatmentGuizhou Medical UniversityGuiyangChina
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic DiseasesGuizhou Medical UniversityGuiyangChina
| | - Yuxia Zhou
- Department of SurgeryAffiliated Hospital of Guizhou Medical UniversityGuiyangChina
- School of Basic Medical SciencesGuizhou Medical UniversityGuiyangChina
- Transformation Engineering Research Center of Chronic Disease Diagnosis and TreatmentGuizhou Medical UniversityGuiyangChina
| | - Li Liang
- School of Basic Medical SciencesGuizhou Medical UniversityGuiyangChina
- Transformation Engineering Research Center of Chronic Disease Diagnosis and TreatmentGuizhou Medical UniversityGuiyangChina
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic DiseasesGuizhou Medical UniversityGuiyangChina
| | - Yunqiao Yang
- School of Basic Medical SciencesGuizhou Medical UniversityGuiyangChina
- Transformation Engineering Research Center of Chronic Disease Diagnosis and TreatmentGuizhou Medical UniversityGuiyangChina
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic DiseasesGuizhou Medical UniversityGuiyangChina
| | - Lifen Xu
- Department of SurgeryAffiliated Hospital of Guizhou Medical UniversityGuiyangChina
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic DiseasesGuizhou Medical UniversityGuiyangChina
| | - Tuo Zhang
- School of Basic Medical SciencesGuizhou Medical UniversityGuiyangChina
- Transformation Engineering Research Center of Chronic Disease Diagnosis and TreatmentGuizhou Medical UniversityGuiyangChina
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic DiseasesGuizhou Medical UniversityGuiyangChina
| | - Po Li
- Department of SurgeryAffiliated Hospital of Guizhou Medical UniversityGuiyangChina
| | - Ting Pan
- School of Basic Medical SciencesGuizhou Medical UniversityGuiyangChina
- Transformation Engineering Research Center of Chronic Disease Diagnosis and TreatmentGuizhou Medical UniversityGuiyangChina
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic DiseasesGuizhou Medical UniversityGuiyangChina
| | - Bing Guo
- School of Basic Medical SciencesGuizhou Medical UniversityGuiyangChina
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic DiseasesGuizhou Medical UniversityGuiyangChina
| | - Tengxiang Chen
- Department of SurgeryAffiliated Hospital of Guizhou Medical UniversityGuiyangChina
- School of Basic Medical SciencesGuizhou Medical UniversityGuiyangChina
- Transformation Engineering Research Center of Chronic Disease Diagnosis and TreatmentGuizhou Medical UniversityGuiyangChina
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic DiseasesGuizhou Medical UniversityGuiyangChina
- Guizhou Institute of Precision MedicineAffiliated Hospital of Guizhou Medical UniversityGuiyangChina
| | - Haiyang Li
- Department of SurgeryAffiliated Hospital of Guizhou Medical UniversityGuiyangChina
- Guizhou Institute of Precision MedicineAffiliated Hospital of Guizhou Medical UniversityGuiyangChina
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16
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Fu Y, Xiang Y, Wu W, Cai J, Tang C, Dong Z. Persistent Activation of Autophagy After Cisplatin Nephrotoxicity Promotes Renal Fibrosis and Chronic Kidney Disease. Front Pharmacol 2022; 13:918732. [PMID: 35707397 PMCID: PMC9189407 DOI: 10.3389/fphar.2022.918732] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 04/26/2022] [Indexed: 11/29/2022] Open
Abstract
Autophagy, a highly conserved catabolic pathway in eukaryotic cells, contributes to the maintenance of the homeostasis and function of the kidney. Upon acute kidney injury (AKI), autophagy is activated in renal tubular cells to act as an intrinsic protective mechanism. However, the role of autophagy in the development of chronic kidney pathologies including renal fibrosis after AKI remains unclear. In this study, we detected a persistent autophagy activation in mouse kidneys after nephrotoxicity of repeated low dose cisplatin (RLDC) treatment. 3-methyladenine (3-MA) and chloroquine (CQ), respective inhibitors of autophagy at the initiation and degradation stages, blocked autophagic flux and improved kidney repair in post-RLDC mice, as indicated by kidney weight, renal function, and less interstitial fibrosis. In vitro, RLDC induced a pro-fibrotic phenotype in renal tubular cells, including the production and secretion of pro-fibrotic cytokines. Notably, autophagy inhibitors blocked RLDC-induced secretion of pro-fibrotic cytokines in these cells. Together, the results indicate that persistent autophagy after AKI induces pro-fibrotic cytokines in renal tubular cells, promoting renal fibrosis and chronic kidney disease.
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Affiliation(s)
- Ying Fu
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, China
| | - Yu Xiang
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, China
| | - Wenwen Wu
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, China
| | - Juan Cai
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, China
| | - Chengyuan Tang
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, China
| | - Zheng Dong
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, China
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, United States
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17
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Molitoris BA. Low-Flow Acute Kidney Injury: The Pathophysiology of Prerenal Azotemia, Abdominal Compartment Syndrome, and Obstructive Uropathy. Clin J Am Soc Nephrol 2022; 17:1039-1049. [PMID: 35584927 PMCID: PMC9269622 DOI: 10.2215/cjn.15341121] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
AKI is a syndrome, not a disease. It results from many different primary and/or secondary etiologies and is often multifactorial, especially in the hospitalized patient. This review discusses the pathophysiology of three etiologies that cause AKI, those being kidney hypoperfusion, abdominal compartment syndrome, and urinary tract obstruction. The pathophysiology of these three causes of AKI differs but is overlapping. They all lead to a low urine flow rate and low urine sodium initially. In all three cases, with early recognition and correction of the underlying process, the resulting functional AKI can be rapidly reversed. However, with continued duration and/or increased severity, cell injury occurs within the kidney, resulting in structural AKI and a longer and more severe disease state with increased morbidity and mortality. This is why early recognition and reversal are critical.
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Affiliation(s)
- Bruce A Molitoris
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, and Department of Anatomy, Cell Biology and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana
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18
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Promsan S, Thongnak L, Pengrattanachot N, Phengpol N, Sutthasupha P, Lungkaphin A. Agomelatine, a structural analog of melatonin, improves kidney dysfunction through regulating the AMPK/mTOR signaling pathway to promote autophagy in obese rats. Food Chem Toxicol 2022; 165:113190. [DOI: 10.1016/j.fct.2022.113190] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 05/20/2022] [Accepted: 05/25/2022] [Indexed: 12/20/2022]
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19
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Klinkhammer BM, Buchtler S, Djudjaj S, Bouteldja N, Palsson R, Edvardsson VO, Thorsteinsdottir M, Floege J, Mack M, Boor P. Current kidney function parameters overestimate kidney tissue repair in reversible experimental kidney disease. Kidney Int 2022; 102:307-320. [PMID: 35483527 DOI: 10.1016/j.kint.2022.02.039] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 01/24/2022] [Accepted: 02/28/2022] [Indexed: 11/24/2022]
Abstract
Although underlying mechanisms and the clinical course of kidney disease progression are well described, less is known about potential disease reversibility. Therefore, to analyze kidney recovery, we adapted a commonly used murine chronic kidney disease (CKD) model of 2,8- dihydroxyadenine (2,8-DHA) crystal-induced nephropathy to study disease recovery and efficacy of disease-modifying interventions. The recovery phase after CKD was characterized by improved kidney function after two weeks which remained stable thereafter. By contrast, even after eight weeks recovery, tubular injury and inflammation were only partially reduced and fibrosis persisted. Deep-learning-based histologic analysis of 8,604 glomeruli and 596,614 tubular cross sections revealed numerous tubules had undergone either prominent dilation or complete atrophy, leading to atubular glomeruli and irreversible nephron loss. We confirmed these findings in a second CKD model, reversible unilateral ureteral obstruction, in which a rapid improvement of glomerular filtration rate during recovery also did not reflect the permanent histologic kidney injury. In 2,8-DHA nephropathy, increased drinking volume was highly effective in disease prevention. However, in therapeutic approaches, high fluid intake was only effective in moderate but not severe CKD and established tissue injury was again poorly reflective of kidney function parameters. The injury was particularly localized in the medulla, which is often not analyzed. Thus, recovery after crystal- or obstruction-induced CKD is characterized by ongoing tissue injury, fibrosis, and nephron loss, but not reflected by standard measures of kidney function. Hence, our data might aid in designing kidney recovery studies and suggest the need for biomarkers specifically monitoring intra-kidney tissue injury.
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Affiliation(s)
| | - Simone Buchtler
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Sonja Djudjaj
- Institute of Pathology, RWTH University Hospital Aachen, Aachen, Germany
| | - Nassim Bouteldja
- Institute of Pathology, RWTH University Hospital Aachen, Aachen, Germany
| | - Runolfur Palsson
- Division of Nephrology, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Vidar Orn Edvardsson
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Children´s Medical Center, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland
| | | | - Jürgen Floege
- Division of Nephrology and Immunology, RWTH University Hospital Aachen, Aachen, Germany
| | - Matthias Mack
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Peter Boor
- Institute of Pathology, RWTH University Hospital Aachen, Aachen, Germany; Division of Nephrology and Immunology, RWTH University Hospital Aachen, Aachen, Germany; Department of Electron Microscopy, RWTH University Hospital Aachen, Aachen, Germany.
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20
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Nayak S, Rathore V, Bharati J, Sahu KK. Extending the ambit of SGLT2 inhibitors beyond diabetes: a review of clinical and preclinical studies on non-diabetic kidney disease. Expert Rev Clin Pharmacol 2022; 14:1513-1526. [PMID: 35020563 DOI: 10.1080/17512433.2021.2028620] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
BACKGROUND Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are novel antidiabetic agents with overwhelming cardiorenal protection. Recent trials focusing on the nephroprotective role of SGLT2i have underscored its success as a phenomenal agent in halting the progression of kidney disease in patients with and without Type 2 diabetes mellitus. Multitudes of pleiotropic effects on tubules have raised hopes for reasonable nephroprotection beyond the purview of the hyperglycemic milieu. AREA COVERED This review summarizes various animal and human data as evidence for the utility of SGLT2i in non-diabetic chronic kidney disease (CKD). Web-based medical database entries were searched. On the premise of existing evidence, we have discussed mechanisms likely contributing to nephroprotection by SGLT2i in patients with non-diabetic CKD. EXPERT OPINION Further elucidation of mechanisms of nephroprotection offered by SGLT2i is required to extend its use as a nephroprotective agent. The use of non-traditional markers of kidney damage in future studies would improve the evaluation of their role in attenuating CKD progression. Emerging animal data support the early use of SGLT2i in states of modest proteinuria for superior outcomes. Future long-term trials in patients should aim to address the time of intervention with SGLT2i during the natural disease course of CKD for best outcomes.
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Affiliation(s)
- Saurabh Nayak
- Department of Nephrology, All India Institute of Medical Science, Raipur, India
| | - Vinay Rathore
- Department of Nephrology, All India Institute of Medical Science, Raipur, India
| | - Joyita Bharati
- Department of Nephrology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
| | - Kamal Kant Sahu
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah Salt Lake City, Zip 84112, Utah, USA
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21
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Higgins CE, Tang J, Higgins SP, Gifford CC, Mian BM, Jones DM, Zhang W, Costello A, Conti DJ, Samarakoon R, Higgins PJ. The Genomic Response to TGF-β1 Dictates Failed Repair and Progression of Fibrotic Disease in the Obstructed Kidney. Front Cell Dev Biol 2021; 9:678524. [PMID: 34277620 PMCID: PMC8284093 DOI: 10.3389/fcell.2021.678524] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 06/07/2021] [Indexed: 12/14/2022] Open
Abstract
Tubulointerstitial fibrosis is a common and diagnostic hallmark of a spectrum of chronic renal disorders. While the etiology varies as to the causative nature of the underlying pathology, persistent TGF-β1 signaling drives the relentless progression of renal fibrotic disease. TGF-β1 orchestrates the multifaceted program of kidney fibrogenesis involving proximal tubular dysfunction, failed epithelial recovery or re-differentiation, capillary collapse and subsequent interstitial fibrosis eventually leading to chronic and ultimately end-stage disease. An increasing complement of non-canonical elements function as co-factors in TGF-β1 signaling. p53 is a particularly prominent transcriptional co-regulator of several TGF-β1 fibrotic-response genes by complexing with TGF-β1 receptor-activated SMADs. This cooperative p53/TGF-β1 genomic cluster includes genes involved in cellular proliferative control, survival, apoptosis, senescence, and ECM remodeling. While the molecular basis for this co-dependency remains to be determined, a subset of TGF-β1-regulated genes possess both p53- and SMAD-binding motifs. Increases in p53 expression and phosphorylation, moreover, are evident in various forms of renal injury as well as kidney allograft rejection. Targeted reduction of p53 levels by pharmacologic and genetic approaches attenuates expression of the involved genes and mitigates the fibrotic response confirming a key role for p53 in renal disorders. This review focuses on mechanisms underlying TGF-β1-induced renal fibrosis largely in the context of ureteral obstruction, which mimics the pathophysiology of pediatric unilateral ureteropelvic junction obstruction, and the role of p53 as a transcriptional regulator within the TGF-β1 repertoire of fibrosis-promoting genes.
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Affiliation(s)
- Craig E. Higgins
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY, United States
| | - Jiaqi Tang
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY, United States
| | - Stephen P. Higgins
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY, United States
| | - Cody C. Gifford
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY, United States
| | - Badar M. Mian
- The Urological Institute of Northeastern New York, Albany, NY, United States
- Division of Urology, Department of Surgery, Albany Medical College, Albany, NY, United States
| | - David M. Jones
- Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, NY, United States
| | - Wenzheng Zhang
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY, United States
| | - Angelica Costello
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY, United States
| | - David J. Conti
- Division of Transplantation Surgery, Department of Surgery, Albany Medical College, Albany, NY, United States
| | - Rohan Samarakoon
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY, United States
| | - Paul J. Higgins
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY, United States
- The Urological Institute of Northeastern New York, Albany, NY, United States
- Division of Urology, Department of Surgery, Albany Medical College, Albany, NY, United States
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22
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Anders HJ, Wilkens L, Schraml B, Marschner J. One concept does not fit all: the immune system in different forms of acute kidney injury. Nephrol Dial Transplant 2021; 36:29-38. [PMID: 32337558 DOI: 10.1093/ndt/gfaa056] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Indexed: 02/06/2023] Open
Abstract
Renal and immune systems maintain body homoeostasis during physiological fluctuations and following tissue injury. The immune system plays a central role during acute kidney injury (AKI), adapting evolutional systems programmed for host defence and minimizing unnecessary collateral damage. Indeed, depending upon the disease context, the impact of the immune system upon the manifestations and consequences of AKI can be quite different. Here we provide an overview of the known and unknown involvement of the immune system within the wide range of different forms of AKI, to oppose oversimplification and to endorse deeper insights into the pathogenesis of the different diseases causing kidney injury. This approach may help to overcome some of the current hurdles in translational AKI research and the development of specific treatments for the different diseases, all presenting with an acute increase in serum creatinine or decline in urinary output. One concept does not fit all.
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Affiliation(s)
- Hans-Joachim Anders
- Department of Medicine IV, Renal Division, University Hospital of the Ludwig Maximilians University, Munich, Germany
| | - Louise Wilkens
- Department of Medicine IV, Renal Division, University Hospital of the Ludwig Maximilians University, Munich, Germany
| | - Barbara Schraml
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, LMU Munich, Planegg-Martinsried, Germany.,Faculty of Medicine, Institute for Cardiovascular Physiology and Pathophysiology, Biomedical Center, LMU Munich, Planegg-Martinsried, Germany
| | - Julian Marschner
- Department of Medicine IV, Renal Division, University Hospital of the Ludwig Maximilians University, Munich, Germany
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23
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Lu M, Li H, Liu W, Zhang X, Li L, Zhou H. Curcumin attenuates renal interstitial fibrosis by regulating autophagy and retaining mitochondrial function in unilateral ureteral obstruction rats. Basic Clin Pharmacol Toxicol 2021; 128:594-604. [PMID: 33354908 DOI: 10.1111/bcpt.13550] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 12/12/2020] [Accepted: 12/21/2020] [Indexed: 12/11/2022]
Abstract
Renal interstitial fibrosis (RIF) is the leading cause of end-stage renal disease, partly because of the lack of effective treatments. Curcumin, the primary active ingredient in turmeric, reportedly exerts potent antifibrotic effects. This study investigated the effects of curcumin on RIF in unilateral ureteral obstruction (UUO) rats and characterized the underlying action mechanism. UUO rats were treated with curcumin for 7 and 14 d. Renal fibrosis was evaluated through haematoxylin-eosin staining, Masson staining, and type I and III collagen expression. Autophagy and mitochondria were observed through scanning electron microscopy. NLRP3 inflammasomes, mitochondria, and autophagy-related proteins were detected through Western blotting. Mitochondrial respiratory enzyme activity was assessed spectrophotometrically. Compared with UUO rats, renal fibrosis was attenuated and NLRP3 inflammasome activation was inhibited in curcumin-treated rats. Furthermore, mitochondrial dysfunction was ameliorated and the LC3B/LC3A ratio and Beclin-1 expression were increased in curcumin-treated rats. Additionally, curcumin inhibited the PI3K/AKT/mTOR pathway. These results indicate that curcumin is a promising treatment agent for RIF, and its antifibrotic effects may be mediated by the inhibition of NLRP3 inflammasome activity through the regulation of autophagy and protection of mitochondrial function in UUO rats.
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Affiliation(s)
- Miaomiao Lu
- Department of Nephrology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Hang Li
- Department of Radiotherapy, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Wenlin Liu
- Department of Nephrology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Xuemei Zhang
- Department of Nephrology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Lili Li
- Department of Nephrology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Hongli Zhou
- Department of Nephrology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
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24
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Tubular mitochondrial AKT1 is activated during ischemia reperfusion injury and has a critical role in predisposition to chronic kidney disease. Kidney Int 2020; 99:870-884. [PMID: 33316281 DOI: 10.1016/j.kint.2020.10.038] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 09/28/2020] [Accepted: 10/02/2020] [Indexed: 12/21/2022]
Abstract
Kidney tubular dysfunction contributes to acute kidney injury and to the transition to chronic kidney disease. Although tubular mitochondria have been implicated in the pathophysiology of kidney failure, the mechanisms are not yet clear. Here, we demonstrated that ischemia-reperfusion injury induced acute translocation and activation of mitochondrial protein kinase B (also known as AKT1) in the kidney tubules. We hypothesized that mitochondrial AKT1 signaling protects against the development of acute kidney injury and subsequent chronic kidney disease. To test this prediction, we generated two novel kidney tubule-specific transgenic mouse strains with inducible expression of mitochondria-targeted dominant negative AKT1 or constitutively active AKT1, using a Cre-Lox strategy. Inhibition of mitochondrial AKT1 in mitochondria-targeted dominant negative AKT1 mice aggravated azotemia, tubular injuries, kidney fibrosis, glomerulosclerosis, and negatively impacted survival after ischemia-reperfusion injury. Conversely, enhancing tubular mitochondrial AKT1 signaling in mitochondria-targeted constitutively active AKT1 mice attenuated kidney injuries, protected kidney function, and significantly improved survival after ischemia-reperfusion injury (76.9% vs. 20.8%, respectively). Uncoupled mitochondrial respiration and increased oxidative stress was found in the kidney tubules when mitochondria AKT1 was inhibited, supporting the role of mitochondrial dysfunction in the pathophysiology of kidney failure. Thus, our studies suggest tubular mitochondrial AKT1 signaling could be a novel target to develop new strategies for better prevention and treatment of kidney injury.
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25
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DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice. Nat Commun 2020; 11:4467. [PMID: 32948751 PMCID: PMC7501299 DOI: 10.1038/s41467-020-18304-z] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 08/10/2020] [Indexed: 02/06/2023] Open
Abstract
Recent studies have reported that upregulation of disulfide-bond A oxidoreductase-like protein (DsbA-L) prevented lipid-induced renal injury in diabetic nephropathy (DN). However, the role and regulation of proximal tubular DsbA-L for renal tubulointerstitial fibrosis (TIF) remains unclear. In current study, we found that a proximal tubules-specific DsbA-L knockout mouse (PT-DsbA-L-KO) attenuated UUO-induced TIF, renal cell apoptosis and inflammation. Mechanistically, the DsbA-L interacted with Hsp90 in mitochondria of BUMPT cells which activated the signaling of Smad3 and p53 to produce connective tissue growth factor (CTGF) and then resulted in accumulation of ECM of BUMPT cells and mouse kidney fibroblasts. In addition, the progression of TIF caused by UUO, ischemic/reperfusion (I/R), aristolochic acid, and repeated acute low-dose cisplatin was also alleviated in PT-DsbA-L-KO mice via the activation of Hsp90 /Smad3 and p53/CTGF axis. Finally, the above molecular changes were verified in the kidney biopsies from patients with obstructive nephropathy (Ob). Together, these results suggest that DsbA-L in proximal tubular cells promotes TIF via activation of the Hsp90 /Smad3 and p53/CTGF axis. DsbA-L upregulation prevents lipid-induced renal injury in diabetic nephropathy. Here, the authors show that DsbA-L knockout attenuates tubulointerstitial fibrosis in mice, and show that this occurs via activation of Smad3 and p53, which result in modulation of CTGF, a regulator of kidney fibrosis.
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26
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Charlton JR, Xu Y, Wu T, deRonde KA, Hughes JL, Dutta S, Oxley GT, Cwiek A, Cathro HP, Charlton NP, Conaway MR, Baldelomar EJ, Parvin N, Bennett KM. Magnetic resonance imaging accurately tracks kidney pathology and heterogeneity in the transition from acute kidney injury to chronic kidney disease. Kidney Int 2020; 99:173-185. [PMID: 32916180 DOI: 10.1016/j.kint.2020.08.021] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 08/07/2020] [Accepted: 08/20/2020] [Indexed: 01/09/2023]
Abstract
Acute kidney injury (AKI) increases the risk for chronic kidney disease (CKD). However, there are few tools to detect microstructural changes after AKI. Here, cationic ferritin-enhanced magnetic resonance imaging (CFE-MRI) was applied to examine the heterogeneity of kidney pathology in the transition from AKI to CKD. Adult male mice received folic acid followed by cationic ferritin and were euthanized at four days (AKI), four weeks (CKD-4) or 12 weeks (CKD-12). Kidneys were examined by histologic methods and CFE-MRI. In the CKD-4 and CKD-12 groups, glomerular number was reduced and atubular cortical lesions were observed. Apparent glomerular volume was larger in the AKI, CKD-4 and CKD-12 groups compared to controls. Glomerular hypertrophy occurred with ageing. Interglomerular distance and glomerular density were combined with other MRI metrics to distinguish the AKI and CKD groups from controls. Despite significant heterogeneity, the noninvasive (MRI-based) metrics were as accurate as invasive (histological) metrics at distinguishing AKI and CKD from controls. To assess the toxicity of cationic ferritin in a CKD model, CKD-4 mice received cationic ferritin and were examined one week later. The CKD-4 groups with and without cationic ferritin were similar, except the iron content of the kidney, liver, and spleen was greater in the CKD-4 plus cationic ferritin group. Thus, our study demonstrates the accuracy and safety of CFE-MRI to detect whole kidney pathology allowing for the development of novel biomarkers of kidney disease and providing a foundation for future in vivo longitudinal studies in mouse models of AKI and CKD to track nephron fate.
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Affiliation(s)
- Jennifer R Charlton
- Department of Pediatrics, Division Nephrology, University of Virginia, Charlottesville, Virginia, USA.
| | - Yanzhe Xu
- ASU-Mayo Center for Innovative Imaging, School of Computing, Informatics, Decision Systems Engineering, Arizona State University, Tempe, Arizona, USA
| | - Teresa Wu
- ASU-Mayo Center for Innovative Imaging, School of Computing, Informatics, Decision Systems Engineering, Arizona State University, Tempe, Arizona, USA
| | - Kim A deRonde
- Department of Pediatrics, Division Nephrology, University of Virginia, Charlottesville, Virginia, USA
| | | | - Shourik Dutta
- School of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Gavin T Oxley
- University of Virginia, Charlottesville, Virginia, USA
| | | | - Helen P Cathro
- Department of Pathology University of Virginia, Charlottesville, Virginia, USA
| | - Nathan P Charlton
- Department of Toxicology, University of Virginia, Virginia, Charlottesville, USA
| | - Mark R Conaway
- Division of Translational Research and Applied Statistics Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA
| | - Edwin J Baldelomar
- Department of Radiology, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Neda Parvin
- Department of Radiology, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Kevin M Bennett
- Department of Radiology, Washington University in St. Louis, St. Louis, Missouri, USA
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27
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Yan Q, Zhu K, Zhang L, Fu Q, Chen Z, Liu S, Fu D, Nakazato R, Yoshioka K, Diao B, Ding G, Li X, Wang H. A negative feedback loop between JNK-associated leucine zipper protein and TGF-β1 regulates kidney fibrosis. Commun Biol 2020; 3:288. [PMID: 32504044 PMCID: PMC7275040 DOI: 10.1038/s42003-020-1008-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 05/17/2020] [Indexed: 12/26/2022] Open
Abstract
Renal fibrosis is controlled by profibrotic and antifibrotic forces. Exploring anti-fibrosis factors and mechanisms is an attractive strategy to prevent organ failure. Here we identified the JNK-associated leucine zipper protein (JLP) as a potential endogenous antifibrotic factor. JLP, predominantly expressed in renal tubular epithelial cells (TECs) in normal human or mouse kidneys, was downregulated in fibrotic kidneys. Jlp deficiency resulted in more severe renal fibrosis in unilateral ureteral obstruction (UUO) mice, while renal fibrosis resistance was observed in TECs-specific transgenic Jlp mice. JLP executes its protective role in renal fibrosis via negatively regulating TGF-β1 expression and autophagy, and the profibrotic effects of ECM production, epithelial-to-mesenchymal transition (EMT), apoptosis and cell cycle arrest in TECs. We further found that TGF-β1 and FGF-2 could negatively regulate the expression of JLP. Our study suggests that JLP plays a central role in renal fibrosis via its negative crosstalk with the profibrotic factor, TGF-β1.
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Affiliation(s)
- Qi Yan
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Zhu
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lu Zhang
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Internal Medicine, and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Qiang Fu
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhaowei Chen
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Shan Liu
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Dou Fu
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ryota Nakazato
- Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan
| | - Katsuji Yoshioka
- Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan
| | - Bo Diao
- Department of Medical Laboratory Center, General Hospital of Central Theater Command, Wuhan, China
| | - Guohua Ding
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaogang Li
- Department of Internal Medicine, and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Huiming Wang
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.
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28
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Stark JE, Opoka AM, Mallela J, Devarajan P, Ma Q, Levinsky NC, Stringer KF, Wong HR, Alder MN. Juvenile OLFM4-null mice are protected from sepsis. Am J Physiol Renal Physiol 2020; 318:F809-F816. [PMID: 32068457 PMCID: PMC7099509 DOI: 10.1152/ajprenal.00443.2019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Pediatric sepsis is a leading cause of morbidity and mortality in children. One of the most common and devastating morbidities is sepsis-related acute kidney injury (AKI). AKI was traditionally thought to be related to low perfusion and acute tubular necrosis. However, little acute tubular necrosis can be found following septic AKI, and little is known about the mechanism of septic AKI. Olfactomedin-4 (OLFM4) is a secreted glycoprotein that marks a subset of neutrophils. Increased expression of OLFM4 in the blood is associated with worse outcomes in sepsis. Here, we investigated a pediatric model of murine sepsis using murine pups to investigate the mechanisms of OLFM4 in sepsis. When sepsis was induced in murine pups, survival was significantly increased in OLFM4-null pups. Immunohistochemistry at 24 h after the induction of sepsis demonstrated increased expression of OLFM4 in the kidney, which was localized to the loop of Henle. Renal cell apoptosis and plasma creatinine were significantly increased in wild-type versus OLFM4-null pups. Finally, bone marrow transplant suggested that increased OLFM4 in the kidney reflects local production rather than filtered from the plasma. These results demonstrate renal expression of OLFM4 for the first time and suggest that a kidney-specific mechanism may contribute to survival differences in OLFM4-null animals.
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Affiliation(s)
- Julie E Stark
- Department of Pediatrics, University of Cincinnati College of Medicine, and Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Amy M Opoka
- Department of Pediatrics, University of Cincinnati College of Medicine, and Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Jaya Mallela
- Department of Pediatrics, University of Cincinnati College of Medicine, and Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Prasad Devarajan
- Division of Nephrology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Qing Ma
- Division of Nephrology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Nick C Levinsky
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Keith F Stringer
- Division of Pathology and Laboratory Medicine, University of Cincinnati Department of Pediatrics, Cincinnati, Ohio
| | - Hector R Wong
- Department of Pediatrics, University of Cincinnati College of Medicine, and Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Matthew N Alder
- Department of Pediatrics, University of Cincinnati College of Medicine, and Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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29
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Landau SI, Guo X, Velazquez H, Torres R, Olson E, Garcia-Milian R, Moeckel GW, Desir GV, Safirstein R. Regulated necrosis and failed repair in cisplatin-induced chronic kidney disease. Kidney Int 2020; 95:797-814. [PMID: 30904067 DOI: 10.1016/j.kint.2018.11.042] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 11/10/2018] [Accepted: 11/21/2018] [Indexed: 12/21/2022]
Abstract
Cisplatin is an effective chemotherapeutic agent, but significant nephrotoxicity limits its clinical use. Despite extensive investigation of the acute cellular and molecular responses to cisplatin, the mechanisms of progression from acute to chronic kidney injury have not been explored. We used functional and morphological metrics to establish a time-point when the transition from acute and reversible kidney injury to chronic and irreparable kidney disease is clearly established. In mice administered 1 or 2 doses of intraperitoneal cisplatin separated by 2 weeks, kidney function returned toward baseline two weeks after the first dose, but failed to return to normal two weeks following a second dose. Multiphoton microscopy revealed increased glomerular epithelial and proximal tubular damage in kidneys exposed to two doses of cisplatin compared with those exposed to a single dose. In contrast, there was no evidence of fibrosis, macrophage invasion, or decrease in endothelial cell mass in chronically diseased kidneys. Pathway analysis of microarray data revealed regulated necrosis as a key determinant in the development of chronic kidney disease after cisplatin administration. Western blot analysis demonstrated activation of proteins involved in necroptosis and increased expression of kidney injury markers, cellular stress response regulators, and upstream activators of regulated necrosis, including Toll-like receptors 2 and 4. These data suggest that unresolved injury and sustained activation of regulated necrosis pathways, rather than fibrosis, promote the progression of cisplatin-induced acute kidney injury to chronic kidney disease.
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Affiliation(s)
- Sarah I Landau
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Medicine, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
| | - Xiaojia Guo
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Heino Velazquez
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Medicine, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
| | - Richard Torres
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Eben Olson
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Rolando Garcia-Milian
- Curriculum and Research Support Department, Cushing/Whitney Medical Library, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Gilbert W Moeckel
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Gary V Desir
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Medicine, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
| | - Robert Safirstein
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Medicine, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA.
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30
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Popper B, Rammer MT, Gasparitsch M, Singer T, Keller U, Döring Y, Lange-Sperandio B. Neonatal obstructive nephropathy induces necroptosis and necroinflammation. Sci Rep 2019; 9:18600. [PMID: 31819111 PMCID: PMC6901532 DOI: 10.1038/s41598-019-55079-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Accepted: 11/21/2019] [Indexed: 12/15/2022] Open
Abstract
Urinary tract obstruction during kidney development causes tubular apoptosis, tubular necrosis, and interstitial inflammation. Necroptosis is a subtype of programmed necrosis mediated by the receptor-interacting serine/threonine-protein kinase-3 (RIPK3) and the pseudokinase mixed lineage kinase domain-like (MLKL). Necrosis induces inflammation and stimulates cell death in an autoamplification loop named necroinflammation. Here, we studied necroptosis and necroinflammation in obstructive nephropathy induced by unilateral ureteral obstruction (UUO) in neonatal C57Bl/6J mice. Ureteral obstruction induced tubular dilatation, tubular basement membrane thickening, cast formation, and increased expression of kidney injury molecule-1 (KIM-1). Morphological investigations showed either apoptotic or necrotic cells in the tubular compartment. Biochemical analysis revealed increased caspase-8 activity and upregulation of RIPK3 as well as phosphorylated-MLKL in UUO-kidneys. Pro-inflammatory cytokines (IL-1α, INF-γ, TNF-α) were upregulated following UUO. Taken together we show that necroptosis and necroinflammation are accompanied phenomena in neonatal kidneys with obstruction. These findings may help to develop novel strategies to treat congenital obstructive nephropathy.
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Affiliation(s)
- Bastian Popper
- Biomedical Center, Core Faciliy Animal Models, Ludwig-Maximilians university, 82152, Martinsried, Germany.,Institute of Pathology, School of Medicine, Technical University of Munich, 81675, Munich, Germany
| | - Marian Theodor Rammer
- Dr. v. Hauner Children's Hospital, Division of Pediatric Nephrology, Ludwig-Maximilians-University, 80337, Munich, Germany
| | - Mojca Gasparitsch
- Dr. v. Hauner Children's Hospital, Division of Pediatric Nephrology, Ludwig-Maximilians-University, 80337, Munich, Germany
| | - Teresa Singer
- Dr. v. Hauner Children's Hospital, Division of Pediatric Nephrology, Ludwig-Maximilians-University, 80337, Munich, Germany
| | - Ursula Keller
- Dr. v. Hauner Children's Hospital, Division of Pediatric Nephrology, Ludwig-Maximilians-University, 80337, Munich, Germany
| | - Yvonne Döring
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, 80336, Munich, Germany.,Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, Bern, Switzerland
| | - Bärbel Lange-Sperandio
- Dr. v. Hauner Children's Hospital, Division of Pediatric Nephrology, Ludwig-Maximilians-University, 80337, Munich, Germany.
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31
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Zhang X, Zhou Y, Yu X, Huang Q, Fang W, Li J, Bonventre JV, Sukhova GK, Libby P, Shi GP. Differential Roles of Cysteinyl Cathepsins in TGF-β Signaling and Tissue Fibrosis. iScience 2019; 19:607-622. [PMID: 31446224 PMCID: PMC6715892 DOI: 10.1016/j.isci.2019.08.014] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 06/11/2019] [Accepted: 08/06/2019] [Indexed: 01/04/2023] Open
Abstract
Transforming growth factor beta (TGF-β) signaling contributes to tissue fibrosis. Here we demonstrate that TGF-β enhances CatS and CatK expression but reduces CatB and CatL expression in mouse kidney tubular epithelial cells (TECs). CatS- and CatK deficiency reduces TEC nuclear membrane importer importin-β expression, Smad-2/3 activation, and extracellular matrix (ECM) production. Yet CatB- and CatL-deficiency displays the opposite observations with reduced nuclear membrane exporter RanBP3 expression. CatS and CatK form immunocomplexes with the importin-β and RanBP3 more effectively than do CatB and CatL. On the plasma membrane, CatS and CatK preferentially form immunocomplexes with and activate TGF-β receptor-2, whereas CatB and CatL form immunocomplexes with and inactivate TGF-β receptor-1. Unilateral ureteral obstruction-induced renal injury tests differential cathepsin activities in TGF-β signaling and tissue fibrosis. CatB- or CatL-deficiency exacerbates fibrosis, whereas CatS- or CatK-deficiency protects kidneys from fibrosis. These cathepsins exert different effects in the TGF-β signaling cascade independent of their proteolytic properties.
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Affiliation(s)
- Xian Zhang
- Department of Medicine, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA; School of Food & Biological Engineering, Hefei University of Technology, Hefei 230009, China
| | - Yi Zhou
- Department of Medicine, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA; Department of Nephrology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Xueqing Yu
- Department of Nephrology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Qin Huang
- Department of Medicine, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA; Department of Rheumatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Wenqian Fang
- Department of Medicine, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA
| | - Jie Li
- Department of Medicine, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA
| | - Joseph V Bonventre
- Department of Medicine, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA
| | - Galina K Sukhova
- Department of Medicine, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA
| | - Peter Libby
- Department of Medicine, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA
| | - Guo-Ping Shi
- Department of Medicine, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA.
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32
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Yang X, Wang H, Tu Y, Li Y, Zou Y, Li G, Wang L, Zhong X. WNT1-inducible signaling protein-1 mediates TGF-β1-induced renal fibrosis in tubular epithelial cells and unilateral ureteral obstruction mouse models via autophagy. J Cell Physiol 2019; 235:2009-2022. [PMID: 31512238 DOI: 10.1002/jcp.29187] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Accepted: 08/26/2019] [Indexed: 12/17/2022]
Abstract
Renal fibrosis is a common pathway for the progression of all chronic kidney diseases to end-stage kidney disease. Studies show that WNT1-inducible signaling pathway protein-1 (WISP-1) is involved in the fibrosis of various organs. The aim of the study was to explore the functional role and potential mechanism of WISP-1 in renal fibrosis. We observed that overexpression of WISP-1 in rat tubular epithelial cells (TECs) enhanced transforming growth factor-β1 (TGF-β1)-induced production of fibrotic markers, including collagen I (Col I), fibronectin (FN) and TGF-β1, while inhibition of WISP-1 suppressed such production. In vivo, the messenger RNA and protein levels of Col I, FN, and α-smooth muscle actin were significantly inhibited after anti-WISP-1 antibody treatment for 7 days in unilateral ureteral obstruction mouse models. Moreover, blockade of WISP-1 by anti-WISP-1 antibody significantly reduced autophagy-related markers, including anti-microtubule-associated protein-1 light chain 3 (LC3) and beclin 1, while increasing sequestosome 1. In addition, overexpression of WISP-1 in TECs increased autophagy as evidenced by greater numbers of GFP-LC3 puncta and increased expression of LC3 and beclin 1 in response to TGF-β1. In contrast, knockdown of WISP-1 by small interfering RNA decreased the number of GFP-LC3 puncta and the expression of LC3 and beclin 1 in TGF-β1-treated TECs. Collectively, these data suggest that WISP-1, as a profibrotic protein, may mediate renal fibrosis by inducing autophagy in both obstructive nephropathy and TGF-β1-treated TECs. WISP-1 may serve as an effective therapeutic target for the treatment of renal fibrosis.
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Affiliation(s)
- Xue Yang
- Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.,Department of Nephrology, Du Jiang Yan Medical Center, Chengdu, China
| | - Huan Wang
- Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.,Department of Clinical Medicine, North Sichuan Medical College, Nanchong, China
| | - Yueju Tu
- Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yi Li
- Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yurong Zou
- Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Guisen Li
- Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Li Wang
- Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiang Zhong
- Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
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33
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Zhong J, Whitman JB, Yang HC, Fogo AB. Mechanisms of Scarring in Focal Segmental Glomerulosclerosis. J Histochem Cytochem 2019; 67:623-632. [PMID: 31116068 PMCID: PMC6713971 DOI: 10.1369/0022155419850170] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 04/22/2019] [Indexed: 01/17/2023] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) presents with scar in parts of some glomeruli and often progresses to global and diffuse glomerulosclerosis. Podocyte injury is the initial target in primary FSGS, induced by a circulating factor. Several gene variants, for example, APOL1, are associated with increased susceptibility to FSGS. Primary FSGS may be due to genetic mutation in key podocyte genes. Increased work stress after loss of nephrons, epigenetic mechanisms, and various profibrotic pathways can contribute to progressive sclerosis, regardless of the initial injury. The progression of FSGS lesions also involves crosstalk between podocytes and other kidney cells, such as parietal epithelial cells, glomerular endothelial cells, and even tubular epithelial cells. New insights related to these mechanisms could potentially lead to new therapeutic strategies to prevent progression of FSGS.
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Affiliation(s)
- Jianyong Zhong
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
- Division of Pediatric Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jacob B Whitman
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Hai-Chun Yang
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
- Division of Pediatric Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Agnes B Fogo
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
- Division of Pediatric Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee
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Li Y, Liu J, Yu T, Yan B, Li H. Interleukin‑33 promotes obstructive renal injury via macrophages. Mol Med Rep 2019; 20:1353-1362. [PMID: 31173201 DOI: 10.3892/mmr.2019.10324] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Accepted: 04/12/2019] [Indexed: 11/05/2022] Open
Abstract
Chronic kidney disease is the outcome of most kidney diseases, and renal fibrosis is a pathological process involved in the progression of these disorders. The role of interleukin (IL)‑33 was previously investigated in fibrotic disorders affecting various organs, including liver, lungs and heart; however, its role in renal fibrosis remains unclear. Previous studies have demonstrated that macrophages are involved in obstructive renal injury. In the present study, the roles of IL‑33 and macrophages on renal fibrosis were investigated using a mouse model of unilateral ureteral obstruction (UUO). Compared with non‑obstructed kidneys, the expression levels of IL‑33 and its receptor, interleukin 1 receptor like 1, increased after UUO. Furthermore, the infiltration of macrophages and the degree of renal fibrosis increased after treatment with IL‑33. Additionally, the expression level of arginase‑1, a marker of M2 macrophages, increased in renal tissue. After depletion of macrophages, the administration of exogenous IL‑33 was not sufficient to reverse the reduction in fibrosis caused by elimination of these cells. Collectively, the present results suggested that IL‑33 promoted renal fibrosis in UUO‑induced renal injury by regulating macrophage polarization.
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Affiliation(s)
- Yanlei Li
- Health Management Medical Center, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Jing Liu
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Ting Yu
- Department of Clinical Laboratory, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Bingdi Yan
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Hongjun Li
- Health Management Medical Center, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
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35
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Gracia-Sancho J, Marrone G, Fernández-Iglesias A. Hepatic microcirculation and mechanisms of portal hypertension. Nat Rev Gastroenterol Hepatol 2019; 16:221-234. [PMID: 30568278 DOI: 10.1038/s41575-018-0097-3] [Citation(s) in RCA: 158] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The liver microcirculatory milieu, mainly composed of liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs) and hepatic macrophages, has an essential role in liver homeostasis, including in preserving hepatocyte function, regulating the vascular tone and controlling inflammation. Liver microcirculatory dysfunction is one of the key mechanisms that promotes the progression of chronic liver disease (also termed cirrhosis) and the development of its major clinical complication, portal hypertension. In the present Review, we describe the current knowledge of liver microcirculatory dysfunction in cirrhotic portal hypertension and appraise the preclinical models used to study the liver circulation. We also provide a comprehensive summary of the promising therapeutic options to target the liver microvasculature in cirrhosis.
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Affiliation(s)
- Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, CIBEREHD, Barcelona, Spain. .,Hepatology, Department of Biomedical Research, Inselspital, Bern University, Bern, Switzerland.
| | - Giusi Marrone
- Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, CIBEREHD, Barcelona, Spain
| | - Anabel Fernández-Iglesias
- Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, CIBEREHD, Barcelona, Spain
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36
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Zhao XC, Livingston MJ, Liang XL, Dong Z. Cell Apoptosis and Autophagy in Renal Fibrosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1165:557-584. [PMID: 31399985 DOI: 10.1007/978-981-13-8871-2_28] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Renal fibrosis is the final common pathway of all chronic kidney diseases progressing to end-stage renal diseases. Autophagy, a highly conserved lysosomal degradation pathway, plays important roles in maintaining cellular homeostasis in all major types of kidney cells including renal tubular cells as well as podocytes, mesangial cells and endothelial cells in glomeruli. Autophagy dysfunction is implicated in the pathogenesis of various renal pathologies. Here, we analyze the pathological role and regulation of autophagy in renal fibrosis and related kidney diseases in both glomeruli and tubulointerstitial compartments. Further research is expected to gain significant mechanistic insights and discover pathway-specific and kidney-selective therapies targeting autophagy to prevent renal fibrosis and related kidney diseases.
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Affiliation(s)
- Xing-Chen Zhao
- Division of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Man J Livingston
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, 30912, USA
| | - Xin-Ling Liang
- Division of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
| | - Zheng Dong
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, 30912, USA.
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37
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Xiao X, Yuan Q, Chen Y, Huang Z, Fang X, Zhang H, Peng L, Xiao P. LncRNA ENST00000453774.1 contributes to oxidative stress defense dependent on autophagy mediation to reduce extracellular matrix and alleviate renal fibrosis. J Cell Physiol 2018; 234:9130-9143. [PMID: 30317629 DOI: 10.1002/jcp.27590] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 09/18/2018] [Indexed: 12/27/2022]
Affiliation(s)
- Xiangcheng Xiao
- Department of Nephrology Xiangya Hospital, Central South University Changsha China
| | - Qiongjing Yuan
- Department of Nephrology Xiangya Hospital, Central South University Changsha China
| | - Yusa Chen
- Department of Nephrology Xiangya Hospital, Central South University Changsha China
| | - Zhihua Huang
- Department of Nephrology Xiangya Hospital, Central South University Changsha China
| | - Xi Fang
- Department of Nephrology Xiangya Hospital, Central South University Changsha China
| | - Haixia Zhang
- Department of Nephrology Xiangya Hospital, Central South University Changsha China
| | - Ling Peng
- The Nephrotic Laboratory, Xiangya Hospital, Central South University Changsha China
| | - Ping Xiao
- Department of Nephrology Xiangya Hospital, Central South University Changsha China
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38
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Jackson AR, Li B, Cohen SH, Ching CB, McHugh KM, Becknell B. The uroplakin plaque promotes renal structural integrity during congenital and acquired urinary tract obstruction. Am J Physiol Renal Physiol 2018; 315:F1019-F1031. [PMID: 29897287 PMCID: PMC6230727 DOI: 10.1152/ajprenal.00173.2018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 05/25/2018] [Accepted: 06/12/2018] [Indexed: 01/16/2023] Open
Abstract
Urinary tract obstruction represents a common cause of kidney injury across the human life span, resulting in chronic kidney disease and end-stage renal disease. Yet, the extent of obstructive renal damage can be heterogeneous between individuals, implying the existence of unknown mechanisms that protect against or accelerate kidney injury. In this study, we investigated the role of urothelial remodeling in renal adaptation during congenital and acquired obstruction. In the Megabladder ( Mgb-/-) model of congenital obstruction and unilateral ureteral ligation model of acute obstruction, progressive hydronephrosis is strongly associated with dynamic reorganization of the renal urothelium, which elaborates a continuous uroplakin (Upk) plaque. This led us to postulate that the Upk plaque prevents parenchymal injury during urinary tract obstruction. To test this hypothesis, we interbred Mgb-/- and Upk1b-/- mice, which lack the critical Upk1b subunit for Upk plaque formation. Upk1b-/-; Mgb-/- mice experienced an accelerated onset of bilateral hydronephrosis with severe (>67%) parenchymal loss, leading to renal failure and mortality in adolescence. To investigate the function of the renal Upk plaque during acute obstruction, we destabilized the Upk plaque by Upk1b deletion or genetically depleted Upk+ cells following unilateral ureteral obstruction. Both of these strategies accelerated renal parenchymal loss following ureteral ligation, attesting to a conserved, stabilizing role for Upk plaque deposition in the acutely obstructed kidney. In aggregate, these complementary experiments provide the first evidence that the Upk plaque confers an essential, protective adaptation to preserve renal parenchymal integrity during congenital and acquired urinary tract obstruction.
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Affiliation(s)
- Ashley R Jackson
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital , Columbus, Ohio
| | - Birong Li
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital , Columbus, Ohio
| | - Shira H Cohen
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital , Columbus, Ohio
| | - Christina B Ching
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital , Columbus, Ohio
- Division of Pediatric Urology, Department of Surgery, Nationwide Children's Hospital , Columbus, Ohio
| | - Kirk M McHugh
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital , Columbus, Ohio
- Department of Anatomy, Ohio State University School of Medicine , Columbus, Ohio
| | - Brian Becknell
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital , Columbus, Ohio
- Nephrology Section, Nationwide Children's Hospital , Columbus, Ohio
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Abstract
Tubular injury sensitizes glomeruli to injury. We review potential mechanisms of this tubuloglomerular cross talk. In the same nephron, tubular injury can cause stenosis of the glomerulotubular junction and finally result in atubular glomeruli. Tubular injury also affects glomerular filtration function through tubuloglomerular feedback. Progenitor cells, that is, parietal epithelial cells and renin positive cells, can be involved in repair of injured glomeruli and also may be modulated by tubular injury. Loss of nephrons induces additional workload and stress on remaining nephrons. Hypoxia and activation of the renin-angiotensin-aldosterone system induced by tubular injury also modulate tubuloglomerular cross talk. Therefore, effective therapies in chronic kidney disease may need to aim to interrupt this deleterious tubuloglomerular cross talk.
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Affiliation(s)
- Jiayi Wang
- 1 Division of Nephrology, Second Xiangya Hospital, Central South University, Changsha, China.,2 Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jianyong Zhong
- 2 Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.,3 Division of Pediatric Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Hai-Chun Yang
- 2 Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.,3 Division of Pediatric Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Agnes B Fogo
- 2 Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.,3 Division of Pediatric Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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40
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Li J, Zhang C, He W, Qiao H, Chen J, Wang K, Oupický D, Sun M. Coordination-driven assembly of catechol-modified chitosan for the kidney-specific delivery of salvianolic acid B to treat renal fibrosis. Biomater Sci 2018; 6:179-188. [PMID: 29170782 DOI: 10.1039/c7bm00811b] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Kidney-specific delivery is critically important for the treatment of renal fibrosis with drugs such as salvianolic acid B (Sal B). Here we report a kidney-specific nanocomplex formed by the coordination-driven assembly of catechol-modified low molecular weight chitosan (HCA-Chi), calcium ions and Sal B. The prepared HCA-Chi-Ca-Sal B (HChi-Ca-Sal B) nanocomplex reversed the TGF-β1-induced epithelial-mesenchymal transition (EMT) in HK-2 cells. In vivo imaging demonstrated a kidney-specific biodistribution of the nanocomplex. The anti-fibrosis effect of HChi-Ca-Sal B was tested in a mouse model of unilateral ureteral obstruction (UUO). Significant attenuation of the morphological lesions and the levels of extracellular matrix (ECM) proteins in the tubulointerstitium was observed in mice treated with HChi-Ca-Sal B, suggesting that the nanocomplex was able to prevent fibrosis better than the treatment with free Sal B. It was concluded that the HChi-Ca-Sal B nanocomplex showed a specific renal targeting capacity and could be utilized to enhance Sal B delivery for treating renal fibrosis.
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Affiliation(s)
- Jing Li
- State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China.
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41
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Yan Q, Song Y, Zhang L, Chen Z, Yang C, Liu S, Yuan X, Gao H, Ding G, Wang H. Autophagy activation contributes to lipid accumulation in tubular epithelial cells during kidney fibrosis. Cell Death Discov 2018; 4:2. [PMID: 30062051 PMCID: PMC6060103 DOI: 10.1038/s41420-018-0065-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 05/14/2018] [Indexed: 12/25/2022] Open
Abstract
Sustained activation of autophagy and lipid accumulation in tubular epithelial cells (TECs) are both associated with the kidney fibrosis progression. Autophagy has been found involved in the lipid metabolism regulation through a bi-directional mechanism of inducing lipolysis as well as promoting lipid droplet formation. However, whether and how autophagy influences lipid accumulation in kidney fibrosis remain unclear. In the current study, we show that UUO-induced lipid accumulation in tubular cells was significantly reduced when the pharmacological inhibitor 3-MA or CQ was administrated both in vivo and in vitro. Of interest, colocalization of LDs and autophagosomes, as well as colocalization of LDs and lysosomes were undetected in UUO-induced fibrotic kidneys, although lysosome function remained robust, indicating the lipid accumulation is lipophagy-lysosome pathway independent. TGF-β1-induced lipid droplets formation in HK-2 cells were decreased when the Beclin-1 expression was silenced, implying that autophagy-upregulated lipid droplets formation is Beclin-1 dependent. Finally, CQ treatment of UUO-induced fibrotic kidneys reduced the expression of α-SMA and tubular cell apoptosis and rescued the expression of E-cadherin, which was associated with the ameliorated lipid deposition. Therefore, our work documented that autophagy promotes lipid droplet formation in TECs in a Beclin-1-dependent manner, which causes renal lipotoxicity and contributes to the progression of kidney fibrosis.
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Affiliation(s)
- Qi Yan
- 1Department of Nephrology, Renmin hospital of Wuhan University, Wuhan, China.,2Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Song
- 1Department of Nephrology, Renmin hospital of Wuhan University, Wuhan, China
| | - Lu Zhang
- 1Department of Nephrology, Renmin hospital of Wuhan University, Wuhan, China
| | - Zhaowei Chen
- 1Department of Nephrology, Renmin hospital of Wuhan University, Wuhan, China
| | - Cheng Yang
- 1Department of Nephrology, Renmin hospital of Wuhan University, Wuhan, China
| | - Shan Liu
- 3Department of Nephrology, University Hospital of Hubei University for Nationalities, Enshi, China
| | - Xiaohan Yuan
- 1Department of Nephrology, Renmin hospital of Wuhan University, Wuhan, China
| | - Hongyu Gao
- 2Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guohua Ding
- 1Department of Nephrology, Renmin hospital of Wuhan University, Wuhan, China
| | - Huiming Wang
- 1Department of Nephrology, Renmin hospital of Wuhan University, Wuhan, China
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Abstract
PURPOSE OF REVIEW Podocytes are critical components of the nephron filtration barrier and are depleted in many kidney injuries and disease states. Terminally differentiated adult podocytes are highly specialized, postmitotic cells, raising the question of whether the body has any ability to regenerate lost podocytes. This timely question has recently been illuminated by a series of innovative studies. Here, we review recent progress on this topic of significant interest and debate. RECENT FINDINGS The innovation of genetic labeling techniques enables fate tracing of individual podocytes, providing the strongest evidence yet that podocytes can be replaced by nearby progenitor cells. In particular, two progenitor pools have recently been identified in multiple studies: parietal epithelial cells and cells of renin lineage. These studies furthermore suggest that podocyte regeneration can be enhanced using ex-vivo or pharmacological interventions. SUMMARY Recent studies indicate that the podocyte compartment is more dynamic than previously believed. Bidirectional exchange with neighboring cellular compartments provides a mechanism for podocyte replacement. Based on these findings, we propose a set of criteria for evaluating podocyte regeneration and suggest that restoration of podocyte number to a subsclerotic threshold be targeted as a potentially achievable clinical goal.
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43
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Yang D, Livingston MJ, Liu Z, Dong G, Zhang M, Chen JK, Dong Z. Autophagy in diabetic kidney disease: regulation, pathological role and therapeutic potential. Cell Mol Life Sci 2018; 75:669-688. [PMID: 28871310 PMCID: PMC5771948 DOI: 10.1007/s00018-017-2639-1] [Citation(s) in RCA: 178] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 08/29/2017] [Accepted: 08/31/2017] [Indexed: 12/17/2022]
Abstract
Diabetic kidney disease, a leading cause of end-stage renal disease, has become a serious public health problem worldwide and lacks effective therapies. Autophagy is a highly conserved lysosomal degradation pathway that removes protein aggregates and damaged organelles to maintain cellular homeostasis. As important stress-responsive machinery, autophagy is involved in the pathogenesis of various diseases. Emerging evidence has suggested that dysregulated autophagy may contribute to both glomerular and tubulointerstitial pathologies in kidneys under diabetic conditions. This review summarizes the recent findings regarding the role of autophagy in the pathogenesis of diabetic kidney disease and highlights the regulation of autophagy by the nutrient-sensing pathways and intracellular stress signaling in this disease. The advances in our understanding of autophagy in diabetic kidney disease will facilitate the discovery of a new therapeutic target for the prevention and treatment of this life-threatening diabetes complication.
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Affiliation(s)
- Danyi Yang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People's Republic of China
| | - Man J Livingston
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, 1459 Laney Walker Blvd, Augusta, GA, 30912, USA
| | - Zhiwen Liu
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People's Republic of China
| | - Guie Dong
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, 1459 Laney Walker Blvd, Augusta, GA, 30912, USA
| | - Ming Zhang
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, 1459 Laney Walker Blvd, Augusta, GA, 30912, USA
| | - Jian-Kang Chen
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, 1459 Laney Walker Blvd, Augusta, GA, 30912, USA
| | - Zheng Dong
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People's Republic of China.
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, 1459 Laney Walker Blvd, Augusta, GA, 30912, USA.
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44
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Yao J, Dai Q, Liu Z, Zhou L, Xu J. Circular RNAs in Organ Fibrosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1087:259-273. [DOI: 10.1007/978-981-13-1426-1_21] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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45
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Jackson L, Woodward M, Coward RJ. The molecular biology of pelvi-ureteric junction obstruction. Pediatr Nephrol 2018; 33:553-571. [PMID: 28286898 PMCID: PMC5859056 DOI: 10.1007/s00467-017-3629-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Revised: 02/16/2017] [Accepted: 02/17/2017] [Indexed: 12/17/2022]
Abstract
Over recent years routine ultrasound scanning has identified increasing numbers of neonates as having hydronephrosis and pelvi-ureteric junction obstruction (PUJO). This patient group presents a diagnostic and management challenge for paediatric nephrologists and urologists. In this review we consider the known molecular mechanisms underpinning PUJO and review the potential of utilising this information to develop novel therapeutics and diagnostic biomarkers to improve the care of children with this disorder.
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Affiliation(s)
- Laura Jackson
- Bristol Renal Group, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK. .,Bristol Royal Hospital for Children, Bristol, UK.
| | - Mark Woodward
- 0000 0004 0399 4960grid.415172.4Bristol Royal Hospital for Children, Bristol, UK
| | - Richard J. Coward
- 0000 0004 1936 7603grid.5337.2Bristol Renal Group, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY UK ,0000 0004 0399 4960grid.415172.4Bristol Royal Hospital for Children, Bristol, UK
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46
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Montford JR, Lehman AMB, Bauer CD, Klawitter J, Klawitter J, Poczobutt JM, Scobey M, Weiser-Evans M, Nemenoff RA, Furgeson SB. Bone marrow-derived cPLA2α contributes to renal fibrosis progression. J Lipid Res 2017; 59:380-390. [PMID: 29229740 DOI: 10.1194/jlr.m082362] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Indexed: 12/17/2022] Open
Abstract
The group IVA calcium-dependent cytosolic phospholipase A2 (cPLA2α) enzyme directs a complex "eicosanoid storm" that accompanies the tissue response to injury. cPLA2α and its downstream eicosanoid mediators are also implicated in the pathogenesis of fibrosis in many organs, including the kidney. We aimed to determine the role of cPLA2α in bone marrow-derived cells in a murine model of renal fibrosis, unilateral ureteral obstruction (UUO). WT C57BL/6J mice were irradiated and engrafted with donor bone marrow from either WT mice [WT-bone marrow transplant (BMT)] or mice deficient in cPLA2α (KO-BMT). After full engraftment, mice underwent UUO and kidneys were collected 3, 7, and 14 days after injury. Using picrosirius red, collagen-3, and smooth muscle α actin staining, we determined that renal fibrosis was significantly attenuated in KO-BMT animals as compared with WT-BMT animals. Lipidomic analysis of homogenized kidneys demonstrated a time-dependent upregulation of pro-inflammatory eicosanoids after UUO; KO-BMT animals had lower levels of many of these eicosanoids. KO-BMT animals also had fewer infiltrating pro-inflammatory CD45+CD11b+Ly6Chi macrophages and reduced message levels of pro-inflammatory cytokines. Our results indicate that cPLA2α and/or its downstream mediators, produced by bone marrow-derived cells, play a major role in eicosanoid production after renal injury and in renal fibrinogenesis.
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Affiliation(s)
- John R Montford
- Department of Medicine, Renal Division, University of Colorado Anschutz Medical Campus, Aurora, CO .,Denver Veterans Affairs Medical Center, Denver, CO
| | - Allison M B Lehman
- Department of Medicine, Renal Division, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Colin D Bauer
- Department of Medicine, Renal Division, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Jelena Klawitter
- Department of Medicine, Renal Division, University of Colorado Anschutz Medical Campus, Aurora, CO.,Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Jost Klawitter
- Department of Medicine, Renal Division, University of Colorado Anschutz Medical Campus, Aurora, CO.,Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Joanna M Poczobutt
- Department of Medicine, Renal Division, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Micah Scobey
- Department of Medicine, Renal Division, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Mary Weiser-Evans
- Department of Medicine, Renal Division, University of Colorado Anschutz Medical Campus, Aurora, CO.,School of Medicine, Consortium for Fibrosis Research and Translation, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Raphael A Nemenoff
- Department of Medicine, Renal Division, University of Colorado Anschutz Medical Campus, Aurora, CO.,School of Medicine, Consortium for Fibrosis Research and Translation, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Seth B Furgeson
- Department of Medicine, Renal Division, University of Colorado Anschutz Medical Campus, Aurora, CO.,School of Medicine, Consortium for Fibrosis Research and Translation, University of Colorado Anschutz Medical Campus, Aurora, CO.,Denver Health and Hospitals, Denver, CO
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47
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Li XY, Wang SS, Han Z, Han F, Chang YP, Yang Y, Xue M, Sun B, Chen LM. Triptolide Restores Autophagy to Alleviate Diabetic Renal Fibrosis through the miR-141-3p/PTEN/Akt/mTOR Pathway. MOLECULAR THERAPY-NUCLEIC ACIDS 2017; 9:48-56. [PMID: 29246323 PMCID: PMC5602517 DOI: 10.1016/j.omtn.2017.08.011] [Citation(s) in RCA: 109] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 08/22/2017] [Accepted: 08/22/2017] [Indexed: 11/04/2022]
Abstract
Fibrosis is the major pathological feature of diabetic kidney disease (DKD). Autophagy, a process to maintain metabolic homeostasis, is obviously inhibited in DKD. Triptolide (TP) is a traditional Chinese medicine extract known for immune suppression and anti-inflammatory and anti-cancer activities. In this study, we investigated the effects of TP on autophagy and fibrosis in DKD. TP restored autophagy and alleviated fibrosis in DKD rats and high-glucose-incubated human mesangial cells. After we applied 3-methyladenine (an autophagy inhibitor) and autophagy-related gene 5-small interfering RNA (siRNA), we found that the improvement of fibrosis on TP was related to the restoration of autophagy. In addition, miR-141-3p levels were increased under high glucose but reduced after TP treatment. miR-141-3p overexpression aggravated the fibrosis and restrained the autophagy further, while miR-141-3p inhibition imitated the effects of TP. As an action target, phosphatase and tensin homolog (PTEN) showed corresponding opposite changes. After PTEN-siRNA transfection, the effects of TP on autophagy and fibrosis were inhibited. PTEN levels were downregulated, with downstream phosphorylated protein kinase B (Akt) and the mammalian target of rapamycin (mTOR) upregulated in high glucose, which were reversed by TP treatment. These findings indicate that TP alleviates fibrosis by restoring autophagy through the miR-141-3p/PTEN/Akt/mTOR pathway and is a novel therapeutic option for DKD.
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Affiliation(s)
- Xiao-Yu Li
- Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China
| | - Shan-Shan Wang
- Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China
| | - Zhe Han
- Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China
| | - Fei Han
- Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China
| | - Yun-Peng Chang
- Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China
| | - Yang Yang
- Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China
| | - Mei Xue
- Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China
| | - Bei Sun
- Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China.
| | - Li-Ming Chen
- Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China.
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48
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Tubulointerstitial fibrosis can sensitize the kidney to subsequent glomerular injury. Kidney Int 2017; 92:1395-1403. [PMID: 28709637 DOI: 10.1016/j.kint.2017.04.010] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 03/21/2017] [Accepted: 04/06/2017] [Indexed: 01/24/2023]
Abstract
Chronic glomerular injury is associated with eventual development of tubulointerstitial fibrosis. Here we aimed to assess whether, and how, mild chronic tubulointerstitial injury affects glomeruli. For this, we generated mice expressing different toxin receptors, one on their proximal tubular epithelial cells (diphtheria toxin receptor [DTR]) and the other only on podocytes (human CD25 [IL-2R] driven by the nephrin promoter [Nep25]), allowing serial induction of tubule-specific and glomerular (podocyte)-specific injury, respectively. Six weeks after diphtheria toxin injection, mild interstitial fibrosis was found in Nep25+/DTR+, but not in Nep25+/DTR- mice. However, atubular glomeruli and neuronal nitric oxide synthase, a mediator of tubuloglomerular feedback, were higher in Nep25+/DTR+ than in DTR- mice and these atubular glomeruli had less podocyte density as assessed by WT-1 biomarker expression. Peritubular capillary density, hypoxia-inducible factor-1 and -2, and cyclooxygenase 2 expression were similar at week six in the two groups. At week seven, all mice were given the immunotoxin LMB-2, which binds to CD25 to induce podocyte injury. Ten days later, proteinuria, podocyte injury, and glomerulosclerosis were more severe in Nep25+/DTR+ than Nep25+/DTR- mice with more severe sclerosis in the tubule-connected glomeruli. This supports the concept that even mild preexisting tubulointerstitial injury sensitizes glomeruli to subsequent podocyte-specific injury. Thus, increased atubular glomeruli and abnormal tubuloglomerular feedback significantly contribute to the crosstalk between the tubulointerstitium and glomeruli.
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Chevalier RL. Evolutionary Nephrology. Kidney Int Rep 2017; 2:302-317. [PMID: 28845468 PMCID: PMC5568830 DOI: 10.1016/j.ekir.2017.01.012] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 01/11/2017] [Accepted: 01/25/2017] [Indexed: 01/05/2023] Open
Abstract
Progressive kidney disease follows nephron loss, hyperfiltration, and incomplete repair, a process described as "maladaptive." In the past 20 years, a new discipline has emerged that expands research horizons: evolutionary medicine. In contrast to physiologic (homeostatic) adaptation, evolutionary adaptation is the result of reproductive success that reflects natural selection. Evolutionary explanations for physiologically maladaptive responses can emerge from mismatch of the phenotype with environment or evolutionary tradeoffs. Evolutionary adaptation to a terrestrial environment resulted in a vulnerable energy-consuming renal tubule and a hypoxic, hyperosmolar microenvironment. Natural selection favors successful energy investment strategy: energy is allocated to maintenance of nephron integrity through reproductive years, but this declines with increasing senescence after ~40 years of age. Risk factors for chronic kidney disease include restricted fetal growth or preterm birth (life history tradeoff resulting in fewer nephrons), evolutionary selection for APOL1 mutations (that provide resistance to trypanosome infection, a tradeoff), and modern life experience (Western diet mismatch leading to diabetes and hypertension). Current advances in genomics, epigenetics, and developmental biology have revealed proximate causes of kidney disease, but attempts to slow kidney disease remain elusive. Evolutionary medicine provides a complementary approach by addressing ultimate causes of kidney disease. Marked variation in nephron number at birth, nephron heterogeneity, and changing susceptibility to kidney injury throughout life history are the result of evolutionary processes. Combined application of molecular genetics, evolutionary developmental biology (evo-devo), developmental programming and life history theory may yield new strategies for prevention and treatment of chronic kidney disease.
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Affiliation(s)
- Robert L. Chevalier
- Department of Pediatrics, The University of Virginia, Charlottesville, Virginia, USA
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Haymann JP, Vinsonneau C, Girshovich A, Daudon M. Insuffisance rénale aiguë obstructive : une lecture physiopathologique. Nephrol Ther 2017; 13 Suppl 1:S1-S5. [DOI: 10.1016/j.nephro.2017.01.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 01/08/2017] [Indexed: 11/27/2022]
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