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Advanced Science (Weinheim,... Nov 2023Podocyte injury plays a critical role in the progression of focal segmental glomerulosclerosis (FSGS). Here, it is reported that B-cell translocation gene 2 (Btg2)...
Podocyte injury plays a critical role in the progression of focal segmental glomerulosclerosis (FSGS). Here, it is reported that B-cell translocation gene 2 (Btg2) promotes Adriamycin (ADR)-induced FSGS via Smad3-dependent podocyte-mesenchymal transition. It is found that in FSGS patients and animal models, Btg2 is markedly upregulated by podocytes and correlated with progressive renal injury. Podocyte-specific deletion of Btg2 protected against the onset of proteinuria and glomerulosclerosis in ADR-treated mice along with inhibition of EMT markers such as α-SMA and vimentin while restoring epithelial marker E-cadherin. In cultured MPC5 podocytes, overexpression of Btg2 largely promoted ADR and TGF-β1-induced EMT and fibrosis, which is further enhanced by overexpressing Btg2 but blocked by disrupting Btg2. Mechanistically, Btg2 is rapidly induced by TGF-β1 and then bound Smad3 but not Smad2 to promote Smad3 signaling and podocyte EMT, which is again exacerbated by overexpressing Btg2 but blocked by deleting Btg2 in MPC5 podocytes. Interestingly, blockade of Smad3 signaling with a Smad3 inhibitor SIS3 is also capable of inhibiting Btg2 expression and Btg2-mediated podocyte EMT, revealing a TGF-β/Smad3-Btg2 circuit mechanism in Btg2-mediated podocyte injury in FSGS. In conclusion, Btg2 is pathogenic in FSGS and promotes podocyte injury via a Smad3-dependent EMT pathway.
Topics: Animals; Humans; Mice; Doxorubicin; Glomerulosclerosis, Focal Segmental; Kidney; Podocytes; Transforming Growth Factor beta; Transforming Growth Factor beta1
PubMed: 37749872
DOI: 10.1002/advs.202304360 -
Frontiers in Bioscience (Landmark... Oct 2023Calcium (Ca2+) plays a critical role in podocyte function. The Ca2+-sensitive receptors on the cell surface can sense changes in Ca2+ concentration, and Ca2+ flow into... (Review)
Review
Calcium (Ca2+) plays a critical role in podocyte function. The Ca2+-sensitive receptors on the cell surface can sense changes in Ca2+ concentration, and Ca2+ flow into podocytes, after activation of Ca2+ channels (such as transient receptor potential canonical (TRPC) channels and N-type calcium channels) by different stimuli. In addition, the type 2 ryanodine receptor (RyR2) and the voltage-dependent anion channel 1 (VDAC1) on mitochondrial store-operated calcium channels (SOCs) on the endoplasmic reticulum maintain the Ca2+ homeostasis of the organelle. Ca2+ signaling is transmitted through multiple downstream signaling pathways and participates in the morphogenesis, structural maintenance, and survival of podocytes. When Ca2+ is dysregulated, it leads to the occurrence and progression of various diseases, such as focal segmental glomerulosclerosis, diabetic kidney disease, lupus nephritis, transplant glomerulopathy, and hypertensive renal injury. Ca2+ signaling is a promising therapeutic target for podocyte-related diseases. This review first summarizes the role of Ca2+ sensing, Ca2+ channels, and different Ca2+-signaling pathways in the biological functions of podocytes, then, explores the status of Ca2+ signaling in different podocyte-related diseases and its advances as a therapeutic target.
Topics: Humans; Podocytes; Calcium Signaling; TRPC6 Cation Channel; Calcium; Diabetic Nephropathies
PubMed: 37919067
DOI: 10.31083/j.fbl2810240 -
Cellular Physiology and Biochemistry :... Apr 2021Podocytes play a vital role in the pathogenesis of nephrotic syndrome (NS), which is clinically characterized by heavy proteinuria, hypoalbuminemia, hyperlipidemia, and... (Review)
Review
Podocytes play a vital role in the pathogenesis of nephrotic syndrome (NS), which is clinically characterized by heavy proteinuria, hypoalbuminemia, hyperlipidemia, and peripheral edema. The pathogenesis of NS has evolved through several hypotheses ranging from immune dysregulation theory and increased glomerular permeability theory to the current concept of podocytopathy. Podocytopathy is characterized by dysfunction or depletion of podocytes, which may be caused by unknown permeability factor, genetic disorders, drugs, infections, systemic disorders, and hyperfiltration. Over the last two decades, numerous studies have been done to explore the molecular mechanisms of podocyte injuries or NS and to develop the novel therapeutic strategies targeting podocytopathy for treatment of NS. Recent studies have shown that normal sphingolipid metabolism is essential for structural and functional integrity of podocytes. As a basic component of the plasma membrane, sphingolipids not only support the assembly of signaling molecules and interaction of receptors and effectors, but also mediate various cellular activities, such as apoptosis, proliferation, stress responses, necrosis, inflammation, autophagy, senescence, and differentiation. This review briefly summarizes current evidence demonstrating the regulation of sphingolipid metabolism in podocytes and the canonical or noncanonical roles of podocyte sphingolipid signaling in the pathogenesis of NS and associated therapeutic strategies.
Topics: Animals; Humans; Metabolic Networks and Pathways; Nephrotic Syndrome; Podocytes; Signal Transduction; Sphingolipids
PubMed: 33861526
DOI: 10.33594/000000356 -
Cells Jul 2020Podocytes are an integral part of the glomerular filtration barrier, a structure that prevents filtration of large proteins and macromolecules into the urine. Podocyte... (Review)
Review
Podocytes are an integral part of the glomerular filtration barrier, a structure that prevents filtration of large proteins and macromolecules into the urine. Podocyte function is dependent on actin cytoskeleton regulation within the foot processes, structures that link podocytes to the glomerular basement membrane. Actin cytoskeleton dynamics in podocyte foot processes are complex and regulated by multiple proteins and other factors. There are two key signal integration and structural hubs within foot processes that regulate the actin cytoskeleton: the slit diaphragm and focal adhesions. Both modulate actin filament extension as well as foot process mobility. No matter what the initial cause, the final common pathway of podocyte damage is dysregulation of the actin cytoskeleton leading to foot process retraction and proteinuria. Disruption of the actin cytoskeleton can be due to acquired causes or to genetic mutations in key actin regulatory and signaling proteins. Here, we describe the major structural and signaling components that regulate the actin cytoskeleton in podocytes as well as acquired and genetic causes of actin dysregulation.
Topics: Actin Cytoskeleton; Actins; Animals; Disease; Focal Adhesions; Humans; Mutation; Podocytes
PubMed: 32708597
DOI: 10.3390/cells9071700 -
Pediatric Nephrology (Berlin, Germany) Sep 2021The selectivity of the glomerular filter is established by physical, chemical, and signaling interplay among its three core constituents: glomerular endothelial cells,... (Review)
Review
The selectivity of the glomerular filter is established by physical, chemical, and signaling interplay among its three core constituents: glomerular endothelial cells, the glomerular basement membrane, and podocytes. Functional impairment or injury of any of these three components can lead to proteinuria. Podocytes are injured in many forms of human and experimental glomerular disease, including minimal change disease, focal segmental glomerulosclerosis, and diabetes mellitus. One of the earliest signs of podocyte injury is loss of their distinct structure, which is driven by dysregulated dynamics of the actin cytoskeleton. The status of the actin cytoskeleton in podocytes depends on a set of actin binding proteins, nucleators and inhibitors of actin polymerization, and regulatory GTPases. Mutations that alter protein function in each category have been implicated in glomerular diseases in humans and animal models. In addition, a growing body of studies suggest that pharmacological modifications of the actin cytoskeleton have the potential to become novel therapeutics for podocyte-dependent chronic kidney diseases. This review presents an overview of the essential proteins that establish actin cytoskeleton in podocytes and studies demonstrating the feasibility of drugging actin cytoskeleton in kidney diseases.
Topics: Actin Cytoskeleton; Animals; Humans; Podocytes
PubMed: 33188449
DOI: 10.1007/s00467-020-04812-z -
Biomedicine & Pharmacotherapy =... Sep 2021Microparticles are a general term for different types of cell plasma membrane-originated vesicles that are released into the extracellular environment. The paracrine... (Review)
Review
Microparticles are a general term for different types of cell plasma membrane-originated vesicles that are released into the extracellular environment. The paracrine action of these nano-sized vesicles is crucial for intercellular communications through the transfer of diverse lipids, cytosolic proteins, RNA as well as microRNAs. The progression of different diseases influences the composition, occurrence, and functions of these cell-derived particles. Podocyte injury has been shown to have an important role in the pathophysiology of many glomerular diseases including IgA nephropathy (IgAN). This review would focus on the possible potential of podocyte-derived microparticles detected in urine to be used as a diagnostic tool in IgAN.
Topics: Animals; Cytoplasmic Vesicles; Glomerulonephritis, IGA; Humans; MicroRNAs; Nanoparticles; Podocytes
PubMed: 34237594
DOI: 10.1016/j.biopha.2021.111891 -
Frontiers in Bioscience (Scholar... Jun 2011We review podocyte molecular structure and function, consider the underlying mechanisms related to podocyte dysfunction and propose that podocyte dysfunction be... (Review)
Review
We review podocyte molecular structure and function, consider the underlying mechanisms related to podocyte dysfunction and propose that podocyte dysfunction be considered in the evaluation and management of age-associated glomerulosclerosis. With aging, progressive sympathetic activation, increased intrarenal renin-angiotensin system (RAS) activity, endothelin system and oxidative stress and reduced nitric oxide (NO)-availability can damage podocytes. Apoptosis and proliferation are the principal podocyte changes following injury with the latter leading to sclerosis and loss of nephrons. Podocyte loss can be evaluated by either determining their average number in biopsed glomeruli or by estimating podocyte number or their associated molecules in urine sediment. Podocyturia may be considered a marker of active glomerular disease. Preliminary data suggest that antiadrenergic drugs, angiotensin converting enzyme (ACE) inhibitors, RAS blocking drugs, endothelin system inhibitors and reduced oxidative stress can protect podocytes. Thus podocytes appear to play an important role in the pathogenesis, evaluation and therapy of age related glomerulosclerosis.
Topics: Adrenergic Antagonists; Aging; Angiotensin-Converting Enzyme Inhibitors; Apoptosis; Endothelins; Glomerulosclerosis, Focal Segmental; Humans; Nitric Oxide; Oxidative Stress; Podocytes; Renin-Angiotensin System
PubMed: 21622249
DOI: 10.2741/204 -
Current Opinion in Nephrology and... May 2017Podocytes are critical components of the nephron filtration barrier and are depleted in many kidney injuries and disease states. Terminally differentiated adult... (Review)
Review
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.
Topics: Animals; Cell Count; Epithelial Cells; Humans; Kidney Diseases; Podocytes; Regeneration; Renin; Stem Cells
PubMed: 28306565
DOI: 10.1097/MNH.0000000000000311 -
Cell and Tissue Research Jul 2017The last 5 years have witnessed tremendous advances in both light- and electron-microscopic techniques in the biomedical sciences. Application of these new cutting-edge... (Review)
Review
The last 5 years have witnessed tremendous advances in both light- and electron-microscopic techniques in the biomedical sciences. Application of these new cutting-edge methods to glomerular biology has advanced considerably and, in part, completed our endeavor to draw a detailed map of the glomerular tuft. The scope of this review is to illustrate these new insights within both the morphometry of podocyte cells and the architecture of the glomerular filtration barrier and to assess whether these findings have indeed had an impact on our biological understanding of glomerular function.
Topics: Animals; Glomerular Basement Membrane; Humans; Podocytes
PubMed: 28283912
DOI: 10.1007/s00441-017-2590-3 -
Molecular Medicine (Cambridge, Mass.) Oct 2023Diabetic kidney disease (DKD) is the main cause of end-stage renal disease, and its clinical manifestations are progressive proteinuria, decreased glomerular filtration... (Review)
Review
Diabetic kidney disease (DKD) is the main cause of end-stage renal disease, and its clinical manifestations are progressive proteinuria, decreased glomerular filtration rate, and renal failure. The injury and death of glomerular podocytes are the keys to DKD. Currently, a variety of cell death modes have been identified in podocytes, including apoptosis, autophagy, endoplasmic reticulum (ER) stress, pyroptosis, necroptosis, ferroptosis, mitotic catastrophe, etc. The signaling pathways leading to these cell death processes are interconnected and can be activated simultaneously or in parallel. They are essential for cell survival and death that determine the fate of cells. With the deepening of the research on the mechanism of cell death, more and more researchers have devoted their attention to the underlying pathologic research and the drug therapy research of DKD. In this paper, we discussed the podocyte physiologic role and DKD processes. We also provide an overview of the types and specific mechanisms involved in each type of cell death in DKD, as well as related targeted therapy methods and drugs are reviewed. In the last part we discuss the complexity and potential crosstalk between various modes of cell death, which will help improve the understanding of podocyte death and lay a foundation for new and ideal targeted therapy strategies for DKD treatment in the future.
Topics: Humans; Diabetic Nephropathies; Podocytes; Cell Death; Apoptosis; Epithelial Cells; Diabetes Mellitus
PubMed: 37828444
DOI: 10.1186/s10020-023-00732-4