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Chronic Kidney Disease: Underlying Molecular Mechanisms

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (5 October 2022) | Viewed by 29399

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Special Issue Editors

Faculty of Health Sciences, University Fernando Pessoa, Rua Carlos da Maia, 4200-150 Porto, Portugal
Interests: toxicology; drugs of abuse; amphetamines; synthetic cathinones; psychoactive substances; toxicometabolomics; cancer metabolomics; biomarkers; hepatotoxicity; nephrotoxicity; cardiotoxicity; oxidative stress
Special Issues, Collections and Topics in MDPI journals
Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
Interests: inflammation; oxidative stress; cardiovascular risk factors; pre-eclampsia; chronic kidney disease; obesity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Chronic kidney disease (CKD), defined as the presence of abnormalities of kidney function or structure lasting at least three months, is an epidemic health issue that requires global attention. The global rise in the incidence of CKD has been accompanied by a general increase in human longevity as well as an increase in the traditional and non-traditional risk factors for the disease. CKD is associated with significant comorbidity and mortality, being responsible for enormous healthcare costs.

An in-depth understanding of the mechanisms of CKD’s onset and progression will enable the implementation of preventive strategies and the development of drugs that have the potential to delay the onset and/or worsening of this disease. Furthermore, proper knowledge of these mechanisms can help in the identification of early biomarkers of this disease, which is crucial for timely clinical intervention.

This Special Issue aims to cover the most recent research findings in the following areas: a) the molecular mechanisms (particularly oxidative stress and inflammation) involved in the pathophysiology of CKD and associated comorbidities; b) the use of emerging methodological approaches—including omics—for unraveling the molecular pathways in CKD and proposing new disease markers; c) mechanisms cross-linking CKD and other health issues, such as cancer, obesity, and diabetes.

Dr. Márcia Carvalho
Dr. Luís Belo
Guest Editors

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Keywords

  • Chronic kidney disease
  • molecular mechanisms
  • oxidative stress
  • inflammation

Published Papers (11 papers)

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Editorial

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3 pages, 215 KiB  
Editorial
Chronic Kidney Disease: Underlying Molecular Mechanisms—A Special Issue Overview
by Luís Belo and Márcia Carvalho
Int. J. Mol. Sci. 2023, 24(15), 12363; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241512363 - 02 Aug 2023
Cited by 2 | Viewed by 799
Abstract
Chronic kidney disease (CKD) is an epidemic health issue that requires global attention [...] Full article
(This article belongs to the Special Issue Chronic Kidney Disease: Underlying Molecular Mechanisms)

Research

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18 pages, 3529 KiB  
Article
Growth Hormone Improves Adipose Tissue Browning and Muscle Wasting in Mice with Chronic Kidney Disease-Associated Cachexia
by Robert H. Mak, Sujana Gunta, Eduardo A. Oliveira and Wai W. Cheung
Int. J. Mol. Sci. 2022, 23(23), 15310; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315310 - 04 Dec 2022
Cited by 10 | Viewed by 2094
Abstract
Cachexia associated with chronic kidney disease (CKD) has been linked to GH resistance. In CKD, GH treatment enhances muscular performance. We investigated the impact of GH on cachexia brought on by CKD. CKD was induced by 5/6 nephrectomy in c57BL/6J mice. After receiving [...] Read more.
Cachexia associated with chronic kidney disease (CKD) has been linked to GH resistance. In CKD, GH treatment enhances muscular performance. We investigated the impact of GH on cachexia brought on by CKD. CKD was induced by 5/6 nephrectomy in c57BL/6J mice. After receiving GH (10 mg/kg/day) or saline treatment for six weeks, CKD mice were compared to sham-operated controls. GH normalized metabolic rate, increased food intake and weight growth, and improved in vivo muscular function (rotarod and grip strength) in CKD mice. GH decreased uncoupling proteins (UCP)s and increased muscle and adipose tissue ATP content in CKD mice. GH decreased lipolysis of adipose tissue by attenuating expression and protein content of adipose triglyceride lipase and protein content of phosphorylated hormone-sensitive lipase in CKD mice. GH reversed the increased expression of beige adipocyte markers (UCP-1, CD137, Tmem26, Tbx1, Prdm16, Pgc1α, and Cidea) and molecules implicated in adipose tissue browning (Cox2/Pgf2α, Tlr2, Myd88, and Traf6) in CKD mice. Additionally, GH normalized the molecular markers of processes connected to muscle wasting in CKD, such as myogenesis and muscle regeneration. By using RNAseq, we previously determined the top 12 skeletal muscle genes differentially expressed between mice with CKD and control animals. These 12 genes’ aberrant expression has been linked to increased muscle thermogenesis, fibrosis, and poor muscle and neuron regeneration. In this study, we demonstrated that GH restored 7 of the top 12 differentially elevated muscle genes in CKD mice. In conclusion, GH might be an effective treatment for muscular atrophy and browning of adipose tissue in CKD-related cachexia. Full article
(This article belongs to the Special Issue Chronic Kidney Disease: Underlying Molecular Mechanisms)
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21 pages, 3198 KiB  
Article
Potential Urine Proteomic Biomarkers for Focal Segmental Glomerulosclerosis and Minimal Change Disease
by Natalia V. Chebotareva, Anatoliy Vinogradov, Alexander G. Brzhozovskiy, Daria N. Kashirina, Maria I. Indeykina, Anna E. Bugrova, Marina Lebedeva, Sergey Moiseev, Evgeny N. Nikolaev and Alexey S. Kononikhin
Int. J. Mol. Sci. 2022, 23(20), 12607; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012607 - 20 Oct 2022
Cited by 10 | Viewed by 1962
Abstract
Primary focal segmental glomerulosclerosis (FSGS), along with minimal change disease (MCD), are diseases with primary podocyte damage that are clinically manifested by the nephrotic syndrome. The pathogenesis of these podocytopathies is still unknown, and therefore, the search for biomarkers of these diseases is [...] Read more.
Primary focal segmental glomerulosclerosis (FSGS), along with minimal change disease (MCD), are diseases with primary podocyte damage that are clinically manifested by the nephrotic syndrome. The pathogenesis of these podocytopathies is still unknown, and therefore, the search for biomarkers of these diseases is ongoing. Our aim was to determine of the proteomic profile of urine from patients with FSGS and MCD. Patients with a confirmed diagnosis of FSGS (n = 30) and MCD (n = 9) were recruited for the study. For a comprehensive assessment of the severity of FSGS a special index was introduced, which was calculated as follows: the first score was assigned depending on the level of eGFR, the second score—depending on the proteinuria level, the third score—resistance to steroid therapy. Patients with the sum of these scores of less than 3 were included in group 1, with 3 or more—in group 2. The urinary proteome was analyzed using liquid chromatography/mass spectrometry. The proteome profiles of patients with severe progressive FSGS from group 2, mild FSGS from group 1 and MCD were compared. Results of the label free analysis were validated using targeted LC-MS based on multiple reaction monitoring (MRM) with stable isotope labelled peptide standards (SIS) available for 47 of the 76 proteins identified as differentiating between at least one pair of groups. Quantitative MRM SIS validation measurements for these 47 proteins revealed 22 proteins with significant differences between at least one of the two group pairs and 14 proteins were validated for both comparisons. In addition, all of the 22 proteins validated by MRM SIS analysis showed the same direction of change as at the discovery stage with label-free LC-MS analysis, i.e., up or down regulation in MCD and FSGS1 against FSGS2. Patients from the FSGS group 2 showed a significantly different profile from both FSGS group 1 and MCD. Among the 47 significantly differentiating proteins, the most significant were apolipoprotein A-IV, hemopexin, vitronectin, gelsolin, components of the complement system (C4b, factors B and I), retinol- and vitamin D-binding proteins. Patients with mild form of FSGS and MCD showed lower levels of Cystatin C, gelsolin and complement factor I. Full article
(This article belongs to the Special Issue Chronic Kidney Disease: Underlying Molecular Mechanisms)
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13 pages, 2830 KiB  
Article
In Vivo Inhibition of TRPC6 by SH045 Attenuates Renal Fibrosis in a New Zealand Obese (NZO) Mouse Model of Metabolic Syndrome
by Zhihuang Zheng, Yao Xu, Ute Krügel, Michael Schaefer, Tilman Grune, Bernd Nürnberg, May-Britt Köhler, Maik Gollasch, Dmitry Tsvetkov and Lajos Markó
Int. J. Mol. Sci. 2022, 23(12), 6870; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126870 - 20 Jun 2022
Cited by 7 | Viewed by 2608
Abstract
Metabolic syndrome is a significant worldwide public health challenge and is inextricably linked to adverse renal and cardiovascular outcomes. The inhibition of the transient receptor potential cation channel subfamily C member 6 (TRPC6) has been found to ameliorate renal outcomes in the unilateral [...] Read more.
Metabolic syndrome is a significant worldwide public health challenge and is inextricably linked to adverse renal and cardiovascular outcomes. The inhibition of the transient receptor potential cation channel subfamily C member 6 (TRPC6) has been found to ameliorate renal outcomes in the unilateral ureteral obstruction (UUO) of accelerated renal fibrosis. Therefore, the pharmacological inhibition of TPRC6 could be a promising therapeutic intervention in the progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome. In the present study, we hypothesized that the novel selective TRPC6 inhibitor SH045 (larixyl N-methylcarbamate) ameliorates UUO-accelerated renal fibrosis in a New Zealand obese (NZO) mouse model, which is a polygenic model of metabolic syndrome. The in vivo inhibition of TRPC6 by SH045 markedly decreased the mRNA expression of pro-fibrotic markers (Col1α1, Col3α1, Col4α1, Acta2, Ccn2, Fn1) and chemokines (Cxcl1, Ccl5, Ccr2) in UUO kidneys of NZO mice compared to kidneys of vehicle-treated animals. Renal expressions of intercellular adhesion molecule 1 (ICAM-1) and α-smooth muscle actin (α-SMA) were diminished in SH045- versus vehicle-treated UUO mice. Furthermore, renal inflammatory cell infiltration (F4/80+ and CD4+) and tubulointerstitial fibrosis (Sirius red and fibronectin staining) were ameliorated in SH045-treated NZO mice. We conclude that the pharmacological inhibition of TRPC6 might be a promising antifibrotic therapeutic method to treat progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome. Full article
(This article belongs to the Special Issue Chronic Kidney Disease: Underlying Molecular Mechanisms)
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14 pages, 17459 KiB  
Article
Kidney Injury Causes Accumulation of Renal Sodium That Modulates Renal Lymphatic Dynamics
by Jing Liu, Elaine L. Shelton, Rachelle Crescenzi, Daniel C. Colvin, Annet Kirabo, Jianyong Zhong, Eric J. Delpire, Hai-Chun Yang and Valentina Kon
Int. J. Mol. Sci. 2022, 23(3), 1428; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031428 - 27 Jan 2022
Cited by 7 | Viewed by 2935
Abstract
Lymphatic vessels are highly responsive to changes in the interstitial environment. Previously, we showed renal lymphatics express the Na-K-2Cl cotransporter. Since interstitial sodium retention is a hallmark of proteinuric injury, we examined whether renal sodium affects NKCC1 expression and the dynamic pumping function [...] Read more.
Lymphatic vessels are highly responsive to changes in the interstitial environment. Previously, we showed renal lymphatics express the Na-K-2Cl cotransporter. Since interstitial sodium retention is a hallmark of proteinuric injury, we examined whether renal sodium affects NKCC1 expression and the dynamic pumping function of renal lymphatic vessels. Puromycin aminonucleoside (PAN)-injected rats served as a model of proteinuric kidney injury. Sodium 23Na/1H-MRI was used to measure renal sodium and water content in live animals. Renal lymph, which reflects the interstitial composition, was collected, and the sodium analyzed. The contractile dynamics of isolated renal lymphatic vessels were studied in a perfusion chamber. Cultured lymphatic endothelial cells (LECs) were used to assess direct sodium effects on NKCC1. MRI showed elevation in renal sodium and water in PAN. In addition, renal lymph contained higher sodium, although the plasma sodium showed no difference between PAN and controls. High sodium decreased contractility of renal collecting lymphatic vessels. In LECs, high sodium reduced phosphorylated NKCC1 and SPAK, an upstream activating kinase of NKCC1, and eNOS, a downstream effector of lymphatic contractility. The NKCC1 inhibitor furosemide showed a weaker effect on ejection fraction in isolated renal lymphatics of PAN vs controls. High sodium within the renal interstitium following proteinuric injury is associated with impaired renal lymphatic pumping that may, in part, involve the SPAK-NKCC1-eNOS pathway, which may contribute to sodium retention and reduce lymphatic responsiveness to furosemide. We propose that this lymphatic vessel dysfunction is a novel mechanism of impaired interstitial clearance and edema in proteinuric kidney disease. Full article
(This article belongs to the Special Issue Chronic Kidney Disease: Underlying Molecular Mechanisms)
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Review

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22 pages, 1694 KiB  
Review
New Insights on the Role of Marinobufagenin from Bench to Bedside in Cardiovascular and Kidney Diseases
by Nazareno Carullo, Giuseppe Fabiano, Mario D'Agostino, Maria Teresa Zicarelli, Michela Musolino, Pierangela Presta, Ashour Michael, Michele Andreucci, Davide Bolignano and Giuseppe Coppolino
Int. J. Mol. Sci. 2023, 24(13), 11186; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241311186 - 06 Jul 2023
Cited by 2 | Viewed by 1287
Abstract
Marinobufagenin (MBG) is a member of the bufadienolide family of compounds, which are natural cardiac glycosides found in a variety of animal species, including man, which have different physiological and biochemical functions but have a common action on the inhibition of the adenosine [...] Read more.
Marinobufagenin (MBG) is a member of the bufadienolide family of compounds, which are natural cardiac glycosides found in a variety of animal species, including man, which have different physiological and biochemical functions but have a common action on the inhibition of the adenosine triphosphatase sodium-potassium pump (Na+/K+-ATPase). MBG acts as an endogenous cardiotonic steroid, and in the last decade, its role as a pathogenic factor in various human diseases has emerged. In this paper, we have collated major evidence regarding the biological characteristics and functions of MBG and its implications in human pathology. This review focused on MBG involvement in chronic kidney disease, including end-stage renal disease, cardiovascular diseases, sex and gender medicine, and its actions on the nervous and immune systems. The role of MBG in pathogenesis and the development of a wide range of pathological conditions indicate that this endogenous peptide could be used in the future as a diagnostic biomarker and/or therapeutic target, opening important avenues of scientific research. Full article
(This article belongs to the Special Issue Chronic Kidney Disease: Underlying Molecular Mechanisms)
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20 pages, 2066 KiB  
Review
The Potential Modulatory Effects of Exercise on Skeletal Muscle Redox Status in Chronic Kidney Disease
by Sara Mendes, Diogo V. Leal, Luke A. Baker, Aníbal Ferreira, Alice C. Smith and João L. Viana
Int. J. Mol. Sci. 2023, 24(7), 6017; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076017 - 23 Mar 2023
Cited by 3 | Viewed by 1455
Abstract
Chronic Kidney Disease (CKD) is a global health burden with high mortality and health costs. CKD patients exhibit lower cardiorespiratory and muscular fitness, strongly associated with morbidity/mortality, which is exacerbated when they reach the need for renal replacement therapies (RRT). Muscle wasting in [...] Read more.
Chronic Kidney Disease (CKD) is a global health burden with high mortality and health costs. CKD patients exhibit lower cardiorespiratory and muscular fitness, strongly associated with morbidity/mortality, which is exacerbated when they reach the need for renal replacement therapies (RRT). Muscle wasting in CKD has been associated with an inflammatory/oxidative status affecting the resident cells’ microenvironment, decreasing repair capacity and leading to atrophy. Exercise may help counteracting such effects; however, the molecular mechanisms remain uncertain. Thus, trying to pinpoint and understand these mechanisms is of particular interest. This review will start with a general background about myogenesis, followed by an overview of the impact of redox imbalance as a mechanism of muscle wasting in CKD, with focus on the modulatory effect of exercise on the skeletal muscle microenvironment. Full article
(This article belongs to the Special Issue Chronic Kidney Disease: Underlying Molecular Mechanisms)
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24 pages, 2278 KiB  
Review
Molecular Mechanisms of Cellular Injury and Role of Toxic Heavy Metals in Chronic Kidney Disease
by Manish Mishra, Larry Nichols, Aditi A. Dave, Elizabeth H Pittman, John P. Cheek, Anasalea J. V. Caroland, Purva Lotwala, James Drummond and Christy C. Bridges
Int. J. Mol. Sci. 2022, 23(19), 11105; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911105 - 21 Sep 2022
Cited by 6 | Viewed by 3232
Abstract
Chronic kidney disease (CKD) is a progressive disease that affects millions of adults every year. Major risk factors include diabetes, hypertension, and obesity, which affect millions of adults worldwide. CKD is characterized by cellular injury followed by permanent loss of functional nephrons. As [...] Read more.
Chronic kidney disease (CKD) is a progressive disease that affects millions of adults every year. Major risk factors include diabetes, hypertension, and obesity, which affect millions of adults worldwide. CKD is characterized by cellular injury followed by permanent loss of functional nephrons. As injured cells die and nephrons become sclerotic, remaining healthy nephrons attempt to compensate by undergoing various structural, molecular, and functional changes. While these changes are designed to maintain appropriate renal function, they may lead to additional cellular injury and progression of disease. As CKD progresses and filtration decreases, the ability to eliminate metabolic wastes and environmental toxicants declines. The inability to eliminate environmental toxicants such as arsenic, cadmium, and mercury may contribute to cellular injury and enhance the progression of CKD. The present review describes major molecular alterations that contribute to the pathogenesis of CKD and the effects of arsenic, cadmium, and mercury on the progression of CKD. Full article
(This article belongs to the Special Issue Chronic Kidney Disease: Underlying Molecular Mechanisms)
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24 pages, 1391 KiB  
Review
Short-Chain Fatty Acids in Chronic Kidney Disease: Focus on Inflammation and Oxidative Stress Regulation
by Giorgia Magliocca, Pasquale Mone, Biagio Raffaele Di Iorio, August Heidland and Stefania Marzocco
Int. J. Mol. Sci. 2022, 23(10), 5354; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105354 - 11 May 2022
Cited by 28 | Viewed by 3231
Abstract
Chronic Kidney Disease (CKD) is a debilitating disease associated with several secondary complications that increase comorbidity and mortality. In patients with CKD, there is a significant qualitative and quantitative alteration in the gut microbiota, which, consequently, also leads to reduced production of beneficial [...] Read more.
Chronic Kidney Disease (CKD) is a debilitating disease associated with several secondary complications that increase comorbidity and mortality. In patients with CKD, there is a significant qualitative and quantitative alteration in the gut microbiota, which, consequently, also leads to reduced production of beneficial bacterial metabolites, such as short-chain fatty acids. Evidence supports the beneficial effects of short-chain fatty acids in modulating inflammation and oxidative stress, which are implicated in CKD pathogenesis and progression. Therefore, this review will provide an overview of the current knowledge, based on pre-clinical and clinical evidence, on the effect of SCFAs on CKD-associated inflammation and oxidative stress. Full article
(This article belongs to the Special Issue Chronic Kidney Disease: Underlying Molecular Mechanisms)
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17 pages, 891 KiB  
Review
Chronic Kidney Disease and Gut Microbiota: What Is Their Connection in Early Life?
by Chien-Ning Hsu and You-Lin Tain
Int. J. Mol. Sci. 2022, 23(7), 3954; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073954 - 02 Apr 2022
Cited by 21 | Viewed by 3940
Abstract
The gut–kidney interaction implicating chronic kidney disease (CKD) has been the focus of increasing interest in recent years. Gut microbiota-targeted therapies could prevent CKD and its comorbidities. Considering that CKD can originate in early life, its treatment and prevention should start in childhood [...] Read more.
The gut–kidney interaction implicating chronic kidney disease (CKD) has been the focus of increasing interest in recent years. Gut microbiota-targeted therapies could prevent CKD and its comorbidities. Considering that CKD can originate in early life, its treatment and prevention should start in childhood or even earlier in fetal life. Therefore, a better understanding of how the early-life gut microbiome impacts CKD in later life and how to develop ideal early interventions are unmet needs to reduce CKD. The purpose of the current review is to summarize (1) the current evidence on the gut microbiota dysbiosis implicated in pediatric CKD; (2) current knowledge supporting the impact of the gut–kidney axis in CKD, including inflammation, immune response, alterations of microbiota compositions, short-chain fatty acids, and uremic toxins; and (3) an overview of the studies documenting early gut microbiota-targeted interventions in animal models of CKD of developmental origins. Treatment options include prebiotics, probiotics, postbiotics, etc. To accelerate the transition of gut microbiota-based therapies for early prevention of CKD, an extended comprehension of gut microbiota dysbiosis implicated in renal programming is needed, as well as a greater focus on pediatric CKD for further clinical translation. Full article
(This article belongs to the Special Issue Chronic Kidney Disease: Underlying Molecular Mechanisms)
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26 pages, 837 KiB  
Review
The Signaling Pathway of TNF Receptors: Linking Animal Models of Renal Disease to Human CKD
by Irina Lousa, Flávio Reis, Alice Santos-Silva and Luís Belo
Int. J. Mol. Sci. 2022, 23(6), 3284; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063284 - 18 Mar 2022
Cited by 16 | Viewed by 4171
Abstract
Chronic kidney disease (CKD) has been recognized as a global public health problem. Despite the current advances in medicine, CKD-associated morbidity and mortality remain unacceptably high. Several studies have highlighted the contribution of inflammation and inflammatory mediators to the development and/or progression of [...] Read more.
Chronic kidney disease (CKD) has been recognized as a global public health problem. Despite the current advances in medicine, CKD-associated morbidity and mortality remain unacceptably high. Several studies have highlighted the contribution of inflammation and inflammatory mediators to the development and/or progression of CKD, such as tumor necrosis factor (TNF)-related biomarkers. The inflammation pathway driven by TNF-α, through TNF receptors 1 (TNFR1) and 2 (TNFR2), involves important mediators in the pathogenesis of CKD. Circulating levels of TNFRs were associated with changes in other biomarkers of kidney function and injury, and were described as predictors of disease progression, cardiovascular morbidity, and mortality in several cohorts of patients. Experimental studies describe the possible downstream signaling pathways induced upon TNFR activation and the resulting biological responses. This review will focus on the available data on TNFR1 and TNFR2, and illustrates their contributions to the pathophysiology of kidney diseases, their cellular and molecular roles, as well as their potential as CKD biomarkers. The emerging evidence shows that TNF receptors could act as biomarkers of renal damage and as mediators of the disease. Furthermore, it has been suggested that these biomarkers could significantly improve the discrimination of clinical CKD prognostic models. Full article
(This article belongs to the Special Issue Chronic Kidney Disease: Underlying Molecular Mechanisms)
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