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The Journal of Histochemistry and... Sep 2019Focal segmental glomerulosclerosis (FSGS) presents with scar in parts of some glomeruli and often progresses to global and diffuse glomerulosclerosis. Podocyte injury is... (Review)
Review
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.
Topics: Animals; Apolipoprotein L1; Cicatrix; Disease Progression; Endothelial Cells; Epigenesis, Genetic; Epithelial Cells; Glomerulosclerosis, Focal Segmental; Humans; Kidney Glomerulus; Kidney Tubules; Podocytes
PubMed: 31116068
DOI: 10.1369/0022155419850170 -
Metabolism: Clinical and Experimental Jan 2024Podocytes are critical for maintaining permselectivity of the glomerular filtration barrier, and podocyte injury is a major cause of proteinuria in various primary and... (Review)
Review
Podocytes are critical for maintaining permselectivity of the glomerular filtration barrier, and podocyte injury is a major cause of proteinuria in various primary and secondary glomerulopathies. Lipid dysmetabolism and inflammatory activation are the distinctive hallmarks of podocyte injury. Lipid accumulation and lipotoxicity trigger cytoskeletal rearrangement, insulin resistance, mitochondrial oxidative stress, and inflammation. Subsequently, inflammation promotes the progression of glomerulosclerosis and renal fibrosis via multiple pathways. These data suggest that lipid dysmetabolism positively or negatively regulates inflammation during podocyte injury. In this review, we summarize recent advances in the understanding of lipid metabolism and inflammation, and highlight the potential association between lipid metabolism and podocyte inflammation.
Topics: Humans; Lipid Metabolism; Podocytes; Proteinuria; Kidney Diseases; Inflammation; Lipids
PubMed: 37925142
DOI: 10.1016/j.metabol.2023.155718 -
Cellular Physiology and Biochemistry :... Sep 2021Protein homeostasis strongly depends on the targeted and selective removal of unneeded or flawed proteins, of protein aggregates, and of damaged or excess organelles by... (Review)
Review
Protein homeostasis strongly depends on the targeted and selective removal of unneeded or flawed proteins, of protein aggregates, and of damaged or excess organelles by the two main intracellular degradative systems, namely the ubiquitin proteasomal system (UPS) and the autophagosomal lysosomal system. Despite representing completely distinct mechanisms of degradation, which underlie differing regulatory mechanisms, growing evidence suggests that the UPS and autophagy strongly interact especially in situations of overwhelming and impairment, and that both are involved in podocyte proteostasis and in the pathogenesis of podocyte injury. The differential impact of autophagy and the UPS on podocyte biology and on podocyte disease development and progression is not understood. Recent advances in understanding the role of the UPS and autophagy in podocyte biology are reviewed here.
Topics: Animals; Autophagosomes; Autophagy; Humans; Kidney Diseases; Lysosomes; Podocytes; Proteasome Endopeptidase Complex; Ubiquitin
PubMed: 34523304
DOI: 10.33594/000000432 -
Nature Reviews. Nephrology Mar 2021Nuclear receptors have a broad spectrum of biological functions in normal physiology and in the pathology of various diseases, including glomerular disease. The primary... (Review)
Review
Nuclear receptors have a broad spectrum of biological functions in normal physiology and in the pathology of various diseases, including glomerular disease. The primary therapies for many glomerular diseases are glucocorticoids, which exert their immunosuppressive and direct podocyte protective effects via the glucocorticoid receptor (GR). As glucocorticoids are associated with important adverse effects and a substantial proportion of patients show resistance to these therapies, the beneficial effects of selective GR modulators are now being explored. Peroxisome proliferator-activated receptor-γ (PPARγ) agonism using thiazolidinediones has potent podocyte cytoprotective and nephroprotective effects. Repurposing of thiazolidinediones or identification of novel PPARγ modulators are potential strategies to treat non-diabetic glomerular disease. Retinoic acid receptor-α is the key mediator of the renal protective effects of retinoic acid, and repair of the endogenous retinoic acid pathway offers another potential therapeutic strategy for glomerular disease. Vitamin D receptor, oestrogen receptor and mineralocorticoid receptor modulators regulate podocyte injury in experimental models. Further studies are needed to better understand the mechanisms of these nuclear receptors, evaluate their synergistic pathways and identify their novel modulators. Here, we focus on the role of nuclear receptors in podocyte biology and non-diabetic glomerular disease.
Topics: Animals; Humans; Kidney Diseases; Kidney Glomerulus; Podocytes; Receptors, Cytoplasmic and Nuclear
PubMed: 32943753
DOI: 10.1038/s41581-020-00339-6 -
Nutrients Oct 2023Nephrotic syndrome (NS) poses a number of nutritional and metabolic problems due to glomerulus injured podocytes, which are responsible for the loss of barrier function,...
Nephrotic syndrome (NS) poses a number of nutritional and metabolic problems due to glomerulus injured podocytes, which are responsible for the loss of barrier function, causing proteinuria, altered fluid and electrolyte balances, and hypoalbuminemia [...].
Topics: Humans; Nephrotic Syndrome; Podocytes; Proteinuria; Epithelial Cells
PubMed: 37960268
DOI: 10.3390/nu15214615 -
Advances in Chronic Kidney Disease Jul 2021The pathobiology of diabetic kidney disease (DKD) involves an interplay between all the many different cell types that exist within the kidney and their shared and... (Review)
Review
The pathobiology of diabetic kidney disease (DKD) involves an interplay between all the many different cell types that exist within the kidney and their shared and cumulative dysfunction in response to chronic hyperglycemia. DKD is characteriszed by morphological changes including tubular hypertrophy, podocyte dysfunction, mesangial expansion and mesangiolysis, endothelitis and capillary rarefaction, arteriolar hyalinosis, basement membrane thickening, and ultimately nephron dropout and tubulointerstitial fibrosis. These adaptive but ultimately maladaptive changes accelerate the progression of lesions in the diabetic kidney by increasing mechanical and oxidative stress, hypoxia, fibrogenesis, inflammation, senescence, and apoptosis. In particular, atrophy at the critical junction between Bowman's capsule and the proximal tubule likely represent the leading cause of nephron dropout and kidney function decline in DKD. Preventing, slowing, or reversing these changes should be the target of future "smart" therapies for patients with DKD, many of which are now under development.
Topics: Diabetes Mellitus; Diabetic Nephropathies; Fibrosis; Humans; Kidney; Kidney Tubules, Proximal; Podocytes
PubMed: 34922684
DOI: 10.1053/j.ackd.2021.07.001 -
American Journal of Physiology. Renal... Mar 2021Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. Besides glycemic and blood pressure control, environmental factors such as cigarette smoking...
Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. Besides glycemic and blood pressure control, environmental factors such as cigarette smoking (CS) adversely affect the progression of DN. The effects of CS on DN progression have been attributed to combustion-generated molecules without consideration to the role of nicotine (NIC), responsible for the addictive properties of both CS and electronic cigarettes (ECs). Podocytes are essential to preserve the structure and function of the glomerular filtration barrier, and strong evidence indicates that early podocyte loss promotes DN progression. We performed experiments in human podocytes and in a mouse model of diabetes that develops nephropathy resembling human DN. We determined that NIC binding to podocytes in concentrations achieved with CS and ECs activated NADPH oxidase, which sets in motion a dysfunctional molecular network integrated by cyclooxygenase 2, known to induce podocyte injury; downregulation of AMP-activated protein kinase, important for maintaining cellular energy stores and antioxidation; and upregulation of CD36, which increased lipid uptake and promoted apoptosis. In diabetic mice, NIC increased proteinuria, a recognized marker of chronic kidney disease progression, accompanied by reduced glomerular podocyte synaptopodin, a crucial stabilizer of the podocyte cytoskeleton, and increased fibronectin expression. This novel study critically implicates NIC itself as a contributor to DN progression in CS and EC users. In this study, we demonstrate that nicotine increases the production of reactive oxygen species, increases cyclooxygenase-2 expression, and upregulates Cd36 while inducing downregulation of AMP-activated protein kinase. In vivo nicotine increases proteinuria and fibronectin expression in diabetic mice. This study demonstrates that effects of nicotine on podocytes are responsible, at least in part, for the deleterious effects of smoking in the progression of chronic kidney disease, including diabetic nephropathy.
Topics: AMP-Activated Protein Kinases; Animals; Apoptosis; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Humans; Mice; Nicotine; Podocytes; Reactive Oxygen Species; Smoking
PubMed: 33459165
DOI: 10.1152/ajprenal.00194.2020 -
Metabolism: Clinical and Experimental Jan 2024Podocyte injury is considered as the most important early event contributing to diabetic kidney disease (DKD). Recent findings provide new insights into the roles of...
BACKGROUND AND AIMS
Podocyte injury is considered as the most important early event contributing to diabetic kidney disease (DKD). Recent findings provide new insights into the roles of lipids and lipid-modulating proteins as key determinants of podocyte function in health and kidney disease. CCDC92, a novel member of coiled-coil domain-containing protein family, was indicated relevant to lipid metabolism, coronary heart disease and type 2 diabetes. However, the expression pattern and role of CCDC92 in the kidney is not clear. This study was designed to elucidate the contribution of CCDC92 in the pathogenesis of DKD.
METHODS
Sections with a pathological diagnosis of different classes of DKD, including subjects with mild DKD (class II, n = 6), subjects with moderate DKD (class III, n = 6) or subjects with severe DKD (class IV, n = 6), and control samples (n = 12) were detected for the expression level of CCDC92 and lipid accumulation. Two types of diabetic mice model (db/db and HFD/STZ) in podocyte-specific Ccdc92 knockout background were generated to clarify the role of CCDC92 in podocyte lipotoxicity.
RESULTS
The level of CCDC92 was increased in renal biopsies sections from patients with DKD, which was correlated with eGFR and lipid accumulation in glomeruli. In animal studies, CCDC92 were also induced in the kidney from two independent diabetic models, especially in podocytes. Podocyte-specific deletion of Ccdc92 ameliorated podocyte injury and ectopic lipid deposition under diabetic condition. Mechanically, CCDC92 promoted podocyte lipotoxicity, at least in part through ABCA1 signaling-mediated lipid homeostasis.
CONCLUSION
Our studies demonstrates that CCDC92 acts as a novel regulator of lipid homeostasis to promote podocyte injury in DKD, suggesting that CCDC92 might be a potential biomarker of podocyte injury in DKD, and targeting CCDC92 may be an effective innovative therapeutic strategy for patients with DKD.
Topics: Animals; Humans; Mice; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Podocytes; Cytoskeletal Proteins; Lipid Metabolism
PubMed: 37952690
DOI: 10.1016/j.metabol.2023.155724 -
Biomolecules Mar 2022Podocytopathies are kidney diseases that are driven by podocyte injury with proteinuria and proteinuria-related symptoms as the main clinical presentations. Albeit... (Review)
Review
Podocytopathies are kidney diseases that are driven by podocyte injury with proteinuria and proteinuria-related symptoms as the main clinical presentations. Albeit podocytopathies are the major contributors to end-stage kidney disease, the underlying molecular mechanisms of podocyte injury remain to be elucidated. Mitochondrial oxidative stress is associated with kidney diseases, and increasing evidence suggests that oxidative stress plays a vital role in the pathogenesis of podocytopathies. Accumulating evidence has placed mitochondrial oxidative stress in the focus of cell death research. Excessive generated reactive oxygen species over antioxidant defense under pathological conditions lead to oxidative damage to cellular components and regulate cell death in the podocyte. Conversely, exogenous antioxidants can protect podocyte from cell death. This review provides an overview of the role of mitochondrial oxidative stress in podocytopathies and discusses its role in the cell death of the podocyte, aiming to identify the novel targets to improve the treatment of patients with podocytopathies.
Topics: Antioxidants; Cell Death; Female; Humans; Kidney Diseases; Male; Oxidative Stress; Podocytes; Proteinuria; Reactive Oxygen Species
PubMed: 35327595
DOI: 10.3390/biom12030403 -
Nature Reviews. Nephrology Jun 2024Podocytes form the backbone of the glomerular filtration barrier and are exposed to various mechanical forces throughout the lifetime of an individual. The highly... (Review)
Review
Podocytes form the backbone of the glomerular filtration barrier and are exposed to various mechanical forces throughout the lifetime of an individual. The highly dynamic biomechanical environment of the glomerular capillaries greatly influences the cell biology of podocytes and their pathophysiology. Throughout the past two decades, a holistic picture of podocyte cell biology has emerged, highlighting mechanobiological signalling pathways, cytoskeletal dynamics and cellular adhesion as key determinants of biomechanical resilience in podocytes. This biomechanical resilience is essential for the physiological function of podocytes, including the formation and maintenance of the glomerular filtration barrier. Podocytes integrate diverse biomechanical stimuli from their environment and adapt their biophysical properties accordingly. However, perturbations in biomechanical cues or the underlying podocyte mechanobiology can lead to glomerular dysfunction with severe clinical consequences, including proteinuria and glomerulosclerosis. As our mechanistic understanding of podocyte mechanobiology and its role in the pathogenesis of glomerular disease increases, new targets for podocyte-specific therapeutics will emerge. Treating glomerular diseases by targeting podocyte mechanobiology might improve therapeutic precision and efficacy, with potential to reduce the burden of chronic kidney disease on individuals and health-care systems alike.
Topics: Podocytes; Humans; Biomechanical Phenomena; Mechanotransduction, Cellular; Cytoskeleton; Biophysics; Animals; Cell Adhesion
PubMed: 38443711
DOI: 10.1038/s41581-024-00815-3