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Nephron. Experimental Nephrology 2007Membranous nephropathy (MN), a major cause of nephrotic syndrome in the adult, is an immune-mediated disease characterized by the accumulation of subepithelial immune... (Review)
Review
BACKGROUND
Membranous nephropathy (MN), a major cause of nephrotic syndrome in the adult, is an immune-mediated disease characterized by the accumulation of subepithelial immune deposits leading to complement activation and podocyte injury. However, the target antigens of circulating antibodies are unknown. Current treatments for patients with MN are entirely empirical, and concept-driven therapies are dramatically lacking.
METHODS
Specificity of circulating antibodies and composition of glomerular deposits were analyzed in Heymann nephritis (HN), a faithful rat model of MN, and in a subset of patients with antenatal MN.
RESULTS
20 years after the identification of megalin as the podocyte target antigen of nephritogenic antibodies in HN, we identified the human counterpart of megalin, the enzymatic podocyte antigen neutral endopeptidase (NEP). Antibodies to megalin or NEP induce formation of subepithelial immune deposits and of C5b-9, the membrane attack complex of complement.
CONCLUSION
It is likely that antigens involved in idiopathic MN are expressed at the podocyte membrane. Their identification together with that of immunodominant epitopes may lead to specific antigen/ epitope-based immunotherapy aimed at inducing specific tolerance.
Topics: Animals; Antigens; Glomerulonephritis, Membranous; Humans; Kidney Glomerulus; Podocytes
PubMed: 17726340
DOI: 10.1159/000107708 -
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 -
Current Opinion in Nephrology and... Jan 2006Podocyte injury is a central event in the development of glomerulosclerosis. This review highlights contributions from the past year to our understanding of mechanisms... (Review)
Review
PURPOSE OF REVIEW
Podocyte injury is a central event in the development of glomerulosclerosis. This review highlights contributions from the past year to our understanding of mechanisms of podocyte injury and implications for potential treatment strategies of glomerular disease.
RECENT FINDINGS
Rearrangement of the actin cytoskeleton, the backbone linking the slit diaphragm, apical domain and sole plate, serves as a common denominator during foot process effacement. Reports on the role of synaptopodin and CDK5 on actin dynamics as well as cathepsin L and B7.1 in subsequent cell migration have expanded our understanding of the podocyte response to injury. Mounting evidence supports an expanding role of the slit diaphragm in signal transduction to mediate downstream cellular responses, including prosurvival effects of the integral proteins nephrin and CD2AP. The discovery that TRPC6 localizes to the slit diaphragm and identification of specific mutations of the transport channel in kindreds of familial focal segmental glomerulosclerosis implicate a causal role for aberrant calcium signaling in podocyte injury. Disruption of the dystroglycan complex, which anchors the podocyte to the underlying basement membrane, in states of foot process effacement may have implications for the recent finding of viable podocytes in the urine in glomerular disease.
SUMMARY
The resurgence of research in podocyte biology over the past decade underscores the importance of this unique cell in preserving glomerular structure and function. A greater understanding of the complex signaling mechanisms governing podocyte biology in health and disease will ultimately lead to novel therapeutic avenues for treating disorders of the podocyte.
Topics: Angiotensin-Converting Enzyme Inhibitors; Cytoskeleton; Glomerular Basement Membrane; Humans; Kidney Diseases; Podocytes; Sialoglycoproteins
PubMed: 16340659
DOI: 10.1097/01.mnh.0000199012.79670.0b -
Nephrology (Carlton, Vic.) Aug 2005The podocyte is a highly specialized cell that plays a key role in regulating the glomerular filtration barrier. A number of advances have been made in recent years,... (Review)
Review
The podocyte is a highly specialized cell that plays a key role in regulating the glomerular filtration barrier. A number of advances have been made in recent years, linked to the discovery of single-gene defects in hereditary glomerular disease, which highlight the role of this cell in preventing proteinuria. This article reviews the molecular biology of the podocyte, focusing on known genetic abnormalities.
Topics: Cell Cycle; Cytoskeleton; Filtration; Humans; Kidney Diseases; Kidney Glomerulus; Morphogenesis; Podocytes; Vascular Endothelial Growth Factor A
PubMed: 16109083
DOI: 10.1111/j.1440-1797.2005.00401.x -
Pflugers Archiv : European Journal of... Aug 2017Membranous nephropathy (MN) is characterized by an accumulation of immune deposits on the subepithelial side of the glomerular basement membrane, which results in... (Review)
Review
Membranous nephropathy (MN) is characterized by an accumulation of immune deposits on the subepithelial side of the glomerular basement membrane, which results in complement activation and proteinuria. Since 2002, several major antigens of the podocyte have been identified in human MN, the first one being neutral endopeptidase (NEP), the alloantigen involved in neonatal cases of MN that occur in newborns from NEP-deficient mothers. This discovery opened the field to the major advances that have occurred since then in the pathophysiology and treatment of MN. It is remarkable that experimental models such as Heymann nephritis and cationic bovine serum albumin-induced MN in the rabbit predicted the pathomechanisms of the human glomerulopathy. The podocyte is at the center of the pathogenesis of MN either by providing a source of endogenous antigens or by creating an environment favorable to deposition and accumulation of immune complexes containing exogenous (non-podocyte) antigens. The podocyte is also a victim of complement activation and antibody blocking activity against enzymes or receptors. A search for innovative drugs aimed at protecting this cell against complement activation and the effects of prolonged ER stress has become a priority.
Topics: Animals; Glomerulonephritis, Membranous; Humans; Neprilysin; Podocytes
PubMed: 28597189
DOI: 10.1007/s00424-017-2007-x -
Journal of the American Society of... Jun 2017Podocyte and glomerular research is center stage for the development of improved preventive and therapeutic strategies for chronic progressive kidney diseases. Held... (Review)
Review
Podocyte and glomerular research is center stage for the development of improved preventive and therapeutic strategies for chronic progressive kidney diseases. Held April 3-6, 2016, the 11th International Podocyte Conference took place in Haifa and Jerusalem, Israel, where participants from all over the world presented their work on new developments in podocyte research. In this review, we briefly highlight the advances made in characterizing the mechanisms involved in podocyte development, metabolism, acquired injury, and repair, including progress in determining the roles of genetic variants and microRNA in particular, as well as the advances made in diagnostic techniques and therapeutics.
Topics: Animals; Biomedical Research; Humans; Kidney Diseases; Kidney Glomerulus; MicroRNAs; Podocytes; Signal Transduction; Stem Cells
PubMed: 28404664
DOI: 10.1681/ASN.2017010027 -
Journal of Investigative Medicine : the... Dec 2017Nephropathy is a major microvascular complication of diabetes mellitus and often leads to terminal renal failure in addition to contributing significantly to... (Review)
Review
Nephropathy is a major microvascular complication of diabetes mellitus and often leads to terminal renal failure in addition to contributing significantly to cardiovascular morbidity and mortality. Despites continuous advances, the pathogenesis of diabetic nephropathy remains poorly understood. Recent studies have underscored the significance of structural and functional changes in podocytes in the development and progression of diabetic nephropathy. The role of podocytes in health and diabetic nephropathy and abnormalities including podocyte hypertrophy, effacement, and apoptosis, and a detailed discussion on the role played by the Wnt-β-catenin signaling pathway in podocyte injury and dysfunction are the focus of this review. In addition, the role played by Wnt signaling in mediating the effects of known therapeutic strategies for diabetic nephropathy is also discussed.
Topics: Animals; Apoptosis; Diabetic Nephropathies; Humans; Hypertrophy; Kidney; Podocytes; Wnt Signaling Pathway
PubMed: 28935636
DOI: 10.1136/jim-2017-000456 -
The International Journal of... Feb 2022As part of the glomerular filtration membrane, podocyte is terminally differentiated, structurally unique, and highly specialized in maintaining kidney function.... (Review)
Review
As part of the glomerular filtration membrane, podocyte is terminally differentiated, structurally unique, and highly specialized in maintaining kidney function. Proteinuria caused by podocyte injury (foot process effacement) is the clinical symptom of various kidney diseases (CKD), including nephrotic syndrome. Podocyte autophagy has become a powerful therapeutic strategy target in ameliorating podocyte injury. Autophagy is known to be associated significantly with sirtuin-1, proteinuria, and podocyte injury. Various key findings in podocyte autophagy were reported in the past ten years, such as the role of endoplasmic reticulum (ER) stress in podocyte autophagy impairment, podocyte autophagy-related gene, essential roles of the signaling pathways: Mammalian Target of Rapamycin (mTOR)/ Phosphoinositide 3-kinase (PI3k)/ serine/threonine kinase 1 (Akt) in podocyte autophagy. These significant factors caused podocyte injury associated with autophagy impairment. Sirtuin-1 was reported to have a vital key role in mTOR signaling, 5'AMP-activated protein kinase (AMPK) regulation, autophagy activation, and various critical pathways associated with podocyte's function and health; it has potential value to podocyte injury pathogenesis investigation. From these findings, podocyte autophagy has become an attractive therapeutic strategy to ameliorate podocyte injury, and this review will provide an in-depth review on therapeutic targets he podocyte autophagy.
Topics: Animals; Autophagy; Disease Models, Animal; Humans; Male; Podocytes; Signal Transduction
PubMed: 34974186
DOI: 10.1016/j.biocel.2021.106153 -
Experimental Biology and Medicine... May 2023Studies over the last decade have markedly broadened our understanding of store-operated Ca channels (SOCs) and their roles in kidney diseases and podocyte dysfunction.... (Review)
Review
Studies over the last decade have markedly broadened our understanding of store-operated Ca channels (SOCs) and their roles in kidney diseases and podocyte dysfunction. Podocytes are terminally differentiated glomerular visceral epithelial cells which are tightly attached to the glomerular capillary basement membrane. Podocytes and their unique foot processes (pedicels) constitute the outer layer of the glomerular filtration membrane and the final barrier preventing filtration of albumin and other plasma proteins. Diabetic nephropathy and other renal diseases are associated with podocyte injury and proteinuria. Recent evidence demonstrates a pivotal role of store-operated Ca entry (SOCE) in maintaining structural and functional integrity of podocytes. This article reviews the current knowledge of SOCE and its contributions to podocyte physiology. Recent studies of the contributions of SOC dysfunction to podocyte injury in both cell culture and animal models are discussed, including work in our laboratory. Several downstream signaling pathways mediating SOC function in podocytes also are examined. Understanding the pivotal roles of SOC in podocyte health and disease is essential, as SOCE-activated signaling pathways are potential treatment targets for podocyte injury-related kidney diseases.
Topics: Animals; Podocytes; Signal Transduction; Models, Animal; Diabetic Nephropathies; Cell Culture Techniques
PubMed: 36533574
DOI: 10.1177/15353702221139187 -
Journal of Diabetes Research 2017Diabetic nephropathy (DN) together with glomerular hyperfiltration has been implicated in the development of diabetic microangiopathy in the initial stage of diabetic... (Review)
Review
Diabetic nephropathy (DN) together with glomerular hyperfiltration has been implicated in the development of diabetic microangiopathy in the initial stage of diabetic diseases. Increased amounts of urinary protein in DN may be associated with functional and morphological alterations of podocyte, mainly including podocyte hypertrophy, epithelial-mesenchymal transdifferentiation (EMT), podocyte detachment, and podocyte apoptosis. Accumulating studies have revealed that disruption in multiple renal signaling pathways had been critical in the progression of these pathological damages, such as adenosine monophosphate-activated kinase signaling pathways (AMPK), wnt/-catenin signaling pathways, endoplasmic reticulum stress-related signaling pathways, mammalian target of rapamycin (mTOR)/autophagy pathway, and Rho GTPases. In this review, we highlight new molecular insights underlying podocyte injury in the progression of DN, which offer new therapeutic targets to develop important renoprotective treatments for DN over the next decade.
Topics: Animals; Apoptosis; Biomedical Research; Cell Adhesion; Diabetic Nephropathies; Epithelial-Mesenchymal Transition; Humans; Podocytes; Prognosis; Proteinuria; Signal Transduction
PubMed: 28791309
DOI: 10.1155/2017/2615286