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Nature Reviews. Disease Primers Aug 2020Podocytopathies are kidney diseases in which direct or indirect podocyte injury drives proteinuria or nephrotic syndrome. In children and young adults, genetic variants... (Review)
Review
Podocytopathies are kidney diseases in which direct or indirect podocyte injury drives proteinuria or nephrotic syndrome. In children and young adults, genetic variants in >50 podocyte-expressed genes, syndromal non-podocyte-specific genes and phenocopies with other underlying genetic abnormalities cause podocytopathies associated with steroid-resistant nephrotic syndrome or severe proteinuria. A variety of genetic variants likely contribute to disease development. Among genes with non-Mendelian inheritance, variants in APOL1 have the largest effect size. In addition to genetic variants, environmental triggers such as immune-related, infection-related, toxic and haemodynamic factors and obesity are also important causes of podocyte injury and frequently combine to cause various degrees of proteinuria in children and adults. Typical manifestations on kidney biopsy are minimal change lesions and focal segmental glomerulosclerosis lesions. Standard treatment for primary podocytopathies manifesting with focal segmental glomerulosclerosis lesions includes glucocorticoids and other immunosuppressive drugs; individuals not responding with a resolution of proteinuria have a poor renal prognosis. Renin-angiotensin system antagonists help to control proteinuria and slow the progression of fibrosis. Symptomatic management may include the use of diuretics, statins, infection prophylaxis and anticoagulation. This Primer discusses a shift in paradigm from patient stratification based on kidney biopsy findings towards personalized management based on clinical, morphological and genetic data as well as pathophysiological understanding.
Topics: Humans; Kidney; Nephrotic Syndrome; Podocytes; Prevalence; Proteinuria
PubMed: 32792490
DOI: 10.1038/s41572-020-0196-7 -
Cell Metabolism Dec 2020Lipid accumulation in podocytes is a major determinant of diabetic kidney disease (DKD) and identification of potential therapeutic targets by mediating podocyte lipid...
Lipid accumulation in podocytes is a major determinant of diabetic kidney disease (DKD) and identification of potential therapeutic targets by mediating podocyte lipid metabolism has clinical importance. This study was to elucidate the role of JAML (junctional adhesion molecule-like protein) in the pathogenesis of DKD. We first confirmed the expression of JAML in podocytes and found that podocyte-specific deletion of Jaml ameliorated podocyte injury and proteinuria in two different models of diabetic mice. We further demonstrated a novel role of JAML in regulating podocyte lipid metabolism through SIRT1-mediated SREBP1 signaling. Similar results were also found in mice with adriamycin-induced nephropathy. Importantly, we observed a higher expression of JAML in glomeruli from subjects with DKD and other types of proteinuric kidney diseases, and the level of JAML was correlated with lipid accumulation and glomerular filtration rate, suggesting that JAML may be an attractive therapeutic target for proteinuric kidney disease.
Topics: Adult; Aged; Animals; Cell Adhesion Molecules; Cell Line; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Female; Humans; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Middle Aged; Podocytes; Rats; Young Adult
PubMed: 33186558
DOI: 10.1016/j.cmet.2020.10.019 -
Journal of the American Society of... Nov 2021The effects of healthy aging on the kidney, and how these effects intersect with superimposed diseases, are highly relevant in the context of the population's increasing... (Review)
Review
The effects of healthy aging on the kidney, and how these effects intersect with superimposed diseases, are highly relevant in the context of the population's increasing longevity. Age-associated changes to podocytes, which are terminally differentiated glomerular epithelial cells, adversely affect kidney health. This review discusses the molecular and cellular mechanisms underlying podocyte aging, how these mechanisms might be augmented by disease in the aged kidney, and approaches to mitigate progressive damage to podocytes. Furthermore, we address how biologic pathways such as those associated with cellular growth confound aging in humans and rodents.
Topics: Adult; Aged; Aging; Animals; Autophagy; Caloric Restriction; Cell Cycle; Cell Shape; Cells, Cultured; Cellular Senescence; DNA Damage; Female; Gene Expression; Humans; Inflammasomes; Kidney Glomerulus; Male; Mice; Middle Aged; Mitochondria; Models, Animal; Oligopeptides; Oxidative Stress; Podocytes; Rats; Regulated Cell Death; Sirtuins; Species Specificity; Young Adult
PubMed: 34716239
DOI: 10.1681/ASN.2021050614 -
Endocrinology Jan 2022Diabetic nephropathy (DN) is the leading cause of kidney failure, with an increasing incidence worldwide. Mitochondrial dysfunction is known to occur in DN and has been... (Review)
Review
Diabetic nephropathy (DN) is the leading cause of kidney failure, with an increasing incidence worldwide. Mitochondrial dysfunction is known to occur in DN and has been implicated in the underlying pathogenesis of disease. These complex organelles have an array of important cellular functions and involvement in signaling pathways, and understanding the intricacies of these responses in health, as well as how they are damaged in disease, is likely to highlight novel therapeutic avenues. A key cell type damaged early in DN is the podocyte, and increasing studies have focused on investigating the role of mitochondria in podocyte injury. This review will summarize what is known about podocyte mitochondrial dynamics in DN, with a particular focus on bioenergetic pathways, highlighting key studies in this field and potential opportunities to target, enhance or protect podocyte mitochondrial function in the treatment of DN.
Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Energy Metabolism; Humans; Mitochondria; Mitochondrial Dynamics; Mitophagy; Podocytes; Signal Transduction; Stress, Physiological
PubMed: 34791124
DOI: 10.1210/endocr/bqab234 -
Clinical Science (London, England :... Apr 2022Albuminuria is the hallmark of both primary and secondary proteinuric glomerulopathies, including focal segmental glomerulosclerosis (FSGS), obesity-related nephropathy,...
Albuminuria is the hallmark of both primary and secondary proteinuric glomerulopathies, including focal segmental glomerulosclerosis (FSGS), obesity-related nephropathy, and diabetic nephropathy (DN). Moreover, albuminuria is an important feature of all chronic kidney diseases (CKDs). Podocytes play a key role in maintaining the permselectivity of the glomerular filtration barrier (GFB) and injury of the podocyte, leading to foot process (FP) effacement and podocyte loss, the unifying underlying mechanism of proteinuric glomerulopathies. The metabolic insult of hyperglycemia is of paramount importance in the pathogenesis of DN, while insults leading to podocyte damage are poorly defined in other proteinuric glomerulopathies. However, shared mechanisms of podocyte damage have been identified. Herein, we will review the role of haemodynamic and oxidative stress, inflammation, lipotoxicity, endocannabinoid (EC) hypertone, and both mitochondrial and autophagic dysfunction in the pathogenesis of the podocyte damage, focussing particularly on their role in the pathogenesis of DN. Gaining a better insight into the mechanisms of podocyte injury may provide novel targets for treatment. Moreover, novel strategies for boosting podocyte repair may open the way to podocyte regenerative medicine.
Topics: Albuminuria; Autophagy; Diabetes Mellitus; Diabetic Nephropathies; Glomerulosclerosis, Focal Segmental; Humans; Podocytes
PubMed: 35415751
DOI: 10.1042/CS20210625 -
The Journal of Clinical Investigation Oct 2020Using the Nephrotic Syndrome Study Network Consortium data set and other publicly available transcriptomic data sets, we identified retinoic acid receptor responder...
Using the Nephrotic Syndrome Study Network Consortium data set and other publicly available transcriptomic data sets, we identified retinoic acid receptor responder protein 1 (RARRES1) as a gene whose expression positively correlated with renal function decline in human glomerular disease. The glomerular expression of RARRES1, which is largely restricted to podocytes, increased in focal segmental glomerulosclerosis (FSGS) and diabetic kidney disease (DKD). TNF-α was a potent inducer of RARRES1 expression in cultured podocytes, and transcriptomic analysis showed the enrichment of cell death pathway genes with RARRES1 overexpression. The overexpression of RARRES1 indeed induced podocyte apoptosis in vitro. Notably, this effect was dependent on its cleavage in the extracellular domain, as the mutation of its cleavage site abolished the apoptotic effect. Mechanistically, the soluble RARRES1 was endocytosed and interacted with and inhibited RIO kinase 1 (RIOK1), resulting in p53 activation and podocyte apoptosis. In mice, podocyte-specific overexpression of RARRES1 resulted in marked glomerular injury and albuminuria, while the overexpression of RARRES1 cleavage mutant had no effect. Conversely, podocyte-specific knockdown of Rarres1 in mice ameliorated glomerular injury in the setting of adriamycin-induced nephropathy. Our study demonstrates an important role and the mechanism of RARRES1 in podocyte injury in glomerular disease.
Topics: Animals; Apoptosis; Cells, Cultured; Diabetic Nephropathies; Disease Models, Animal; Disease Progression; Gene Knockdown Techniques; Glomerulosclerosis, Focal Segmental; Humans; Kidney Glomerulus; Membrane Proteins; Mice; Mice, Transgenic; Mutant Proteins; Podocytes; RNA, Messenger; Signal Transduction; Solubility; Tumor Necrosis Factor-alpha; Up-Regulation
PubMed: 32634130
DOI: 10.1172/JCI140155 -
The New England Journal of Medicine Apr 2021
Review
Topics: Albuminuria; Autoimmunity; Glomerular Basement Membrane; Glomerular Filtration Rate; Humans; Kidney Glomerulus; Podocytes; Renal Insufficiency, Chronic
PubMed: 33852781
DOI: 10.1056/NEJMra1808786 -
Cell Death & Disease Sep 2021Podocytes are known to play a determining role in the progression of proteinuric kidney disease. N-methyladenosine (m6A), as the most abundant chemical modification in...
Podocytes are known to play a determining role in the progression of proteinuric kidney disease. N-methyladenosine (m6A), as the most abundant chemical modification in eukaryotic mRNA, has been reported to participate in various pathological processes. However, its role in podocyte injury remains unclear. In this study, we observed the elevated m6A RNA levels and the most upregulated METTL14 expression in kidneys of mice with adriamycin (ADR) and diabetic nephropathy. METTL14 was also evidently increased in renal biopsy samples from patients with focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy and in cultured human podocytes with ADR or advanced glycation end product (AGE) treatment in vitro. Functionally, we generated mice with podocyte-specific METTL14 deletion, and identified METTL14 knockout in podocytes improved glomerular function and alleviated podocyte injury, characterized by activation of autophagy and inhibition of apoptosis and inflammation, in mice with ADR nephropathy. Similar to the results in vivo, knockdown of METTL14 facilitated autophagy and alleviated apoptosis and inflammation in podocytes under ADR or AGE condition in vitro. Mechanically, we identified METTL14 knockdown upregulated the level of Sirt1, a well-known protective deacetylase in proteinuric kidney diseases, in podocytes with ADR or AGE treatment. The results of MeRIP-qPCR and dual-luciferase reporter assay indicated METTL14 promoted Sirt1 mRNA m6A modification and degradation in injured podocytes. Our findings suggest METTL14-dependent RNA m6A modification contributes to podocyte injury through posttranscriptional regulation of Sirt1 mRNA, which provide a potential approach for the diagnosis and treatment of podocytopathies.
Topics: Adenosine; Animals; Apoptosis; Autophagy; Cytoprotection; Diabetic Nephropathies; Disease Progression; Down-Regulation; Doxorubicin; Gene Silencing; Glycation End Products, Advanced; Inflammation; Male; Methyltransferases; Mice, Inbred C57BL; Models, Biological; Podocytes; RNA, Messenger; Sirtuin 1; Up-Regulation; Mice
PubMed: 34580283
DOI: 10.1038/s41419-021-04156-y -
Kidney360 Dec 2023As the population in many industrial countries is aging, the risk, incidence, and prevalence of CKD increases. In the kidney, advancing age results in a progressive... (Review)
Review
As the population in many industrial countries is aging, the risk, incidence, and prevalence of CKD increases. In the kidney, advancing age results in a progressive decrease in nephron number and an increase in glomerulosclerosis. In this review, we focus on the effect of aging on glomerular podocytes, the post-mitotic epithelial cells critical for the normal integrity and function of the glomerular filtration barrier. The podocytes undergo senescence and transition to a senescence-associated secretory phenotype typified by the production and secretion of inflammatory cytokines that can influence neighboring glomerular cells by paracrine signaling. In addition to senescence, the aging podocyte phenotype is characterized by ultrastructural and functional changes; hypertrophy; cellular, oxidative, and endoplasmic reticulum stress; reduced autophagy; and increased expression of aging genes. This results in a reduced podocyte health span and a shortened life span. Importantly, these changes in the pathways/processes characteristic of healthy podocyte aging are also often similar to pathways in the disease-induced injured podocyte. Finally, the better understanding of podocyte aging and senescence opens therapeutic options to slow the rate of podocyte aging and promote kidney health.
Topics: Humans; Podocytes; Aging; Kidney Glomerulus; Kidney Diseases; Epithelial Cells
PubMed: 37950369
DOI: 10.34067/KID.0000000000000284 -
Kidney International Mar 2024Complement activation has long been recognized as a central feature of membranous nephropathy (MN). Evidence for its role has been derived from the detection of... (Review)
Review
Complement activation has long been recognized as a central feature of membranous nephropathy (MN). Evidence for its role has been derived from the detection of complement products in biopsy tissue and urine from patients with MN and from mechanistic studies primarily based on the passive Heymann nephritis model. Only recently, more detailed insights into the exact mechanisms of complement activation and effector pathways have been gained from patient data, animal models, and in vitro models based on specific target antigens relevant to the human disease. These data are of clinical relevance, as they parallel the recent development of numerous specific complement therapeutics for clinical use. Despite efficient B-cell depletion, many patients with MN achieve only partial remission of proteinuria, which may be explained by the persistence of subepithelial immune complexes and ongoing complement-mediated podocyte injury. Targeting complement, therefore, represents an attractive adjunct treatment for MN, but it will need to be tailored to the specific complement pathways relevant to MN. This review summarizes the different lines of evidence for a central role of complement in MN and for the relevance of distinct complement activation and effector pathways, with a focus on recent developments.
Topics: Animals; Humans; Glomerulonephritis, Membranous; Complement Activation; Podocytes; Complement System Proteins; Antigen-Antibody Complex
PubMed: 38142037
DOI: 10.1016/j.kint.2023.10.035