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Frontiers in Immunology 2023The glomerular filtration barrier, comprising the inner layer of capillary fenestrated endothelial cells, outermost podocytes, and the glomerular basement membrane... (Review)
Review
The glomerular filtration barrier, comprising the inner layer of capillary fenestrated endothelial cells, outermost podocytes, and the glomerular basement membrane between them, plays a pivotal role in kidney function. Podocytes, terminally differentiated epithelial cells, are challenging to regenerate once injured. They are essential for maintaining the integrity of the glomerular filtration barrier. Damage to podocytes, resulting from intrinsic or extrinsic factors, leads to proteinuria in the early stages and eventually progresses to chronic kidney disease (CKD). Immune-mediated podocyte injury is a primary pathogenic mechanism in proteinuric glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and lupus nephritis with podocyte involvement. An extensive body of evidence indicates that podocytes not only contribute significantly to the maintenance of the glomerular filtration barrier and serve as targets of immune responses but also exhibit immune cell-like characteristics, participating in both innate and adaptive immunity. They play a pivotal role in mediating glomerular injury and represent potential therapeutic targets for CKD. This review aims to systematically elucidate the mechanisms of podocyte immune injury in various podocyte lesions and provide an overview of recent advances in podocyte immunotherapy. It offers valuable insights for a deeper understanding of the role of podocytes in proteinuric glomerular diseases, and the identification of new therapeutic targets, and has significant implications for the future clinical diagnosis and treatment of podocyte-related disorders.
Topics: Humans; Podocytes; Endothelial Cells; Glomerular Basement Membrane; Renal Insufficiency, Chronic; Immunity
PubMed: 38288116
DOI: 10.3389/fimmu.2023.1335936 -
International Journal of Molecular... Dec 2020Gangliosides constitute a subgroup of glycosphingolipids characterized by the presence of sialic acid residues in their structure. As constituents of cellular membranes,... (Review)
Review
Gangliosides constitute a subgroup of glycosphingolipids characterized by the presence of sialic acid residues in their structure. As constituents of cellular membranes, in particular of raft microdomains, they exert multiple functions, some of them capital in cell homeostasis. Their presence in cells is tightly regulated by a balanced expression and function of the enzymes responsible for their biosynthesis, ganglioside synthases, and their degradation, glycosidases. The dysregulation of their abundance results in rare and common diseases. In this review, we make a point on the relevance of gangliosides and some of their metabolic precursors, such as ceramides, in the function of podocytes, the main cellular component of the glomerular filtration barrier, as well as their implications in podocytopathies. The results presented in this review suggest the pertinence of clinical lipidomic studies targeting these metabolites.
Topics: Animals; Cell Membrane; Gangliosides; Glomerular Filtration Barrier; Humans; Podocytes
PubMed: 33348903
DOI: 10.3390/ijms21249645 -
Tissue Engineering. Part B, Reviews Aug 2022Unraveling the complex behavior of healthy and disease podocytes by analyzing the changes in their unique arrangement of foot processes, slit diaphragm, and the... (Review)
Review
Unraveling the complex behavior of healthy and disease podocytes by analyzing the changes in their unique arrangement of foot processes, slit diaphragm, and the three-dimensional (3D) morphology is a long-standing goal in kidney-glomerular research. The complexities surrounding the podocytes' accessibility in animal models and growing evidence of differences between humans and animal systems have compelled researchers to look for alternate approaches to study podocyte behaviors. With the advent of bioengineered models, an increasingly powerful and diverse set of tools is available to develop novel podocyte culture systems. This review discusses the pertinence of various culture models of podocytes to study podocyte mechanisms in both normal physiology and disease conditions. While no one system comprehensively recapitulates podocytes' architecture, we emphasize how the existing systems can be exploited to answer targeted questions on podocyte structure and function. We highlight the distinct advantages and limitations of using these models to study podocyte behaviors and screen therapeutics. Finally, we discuss various considerations and potential engineering strategies for developing next-generation complex 3D culture models for studying podocyte behaviors . Impact Statement In various glomerular kidney diseases, there are numerous alterations in podocyte structure and function. Yet, many of these disease events and the required targeted therapies remain unknown, resulting in nonspecific treatments. The scientific and clinical communities actively search for new modes to develop structurally and functionally relevant podocyte culture systems to gain insights into various diseases and develop therapeutics. Current systems help in some ways but are not sufficient. A deeper understanding of these previous approaches is essential to advance the field, and importantly, bioengineering strategies can contribute a unique toolbox to establish next-generation podocyte systems.
Topics: Animals; Bioengineering; Humans; Kidney; Kidney Glomerulus; Podocytes
PubMed: 34541902
DOI: 10.1089/ten.TEB.2021.0154 -
Frontiers in Immunology 2023Focal segmental glomerulosclerosis (FSGS) is a common glomerular disorder that manifests clinically with the nephrotic syndrome and has a propensity to recur following... (Review)
Review
Focal segmental glomerulosclerosis (FSGS) is a common glomerular disorder that manifests clinically with the nephrotic syndrome and has a propensity to recur following kidney transplantation. The pathophysiology and therapies available to treat FSGS currently remain elusive. Since the podocyte appears to be the target of apparent circulating factor(s) that lead to recurrence of proteinuria following kidney transplantation, this article is focused on the podocyte. In the context of kidney transplantation, the performance of pre- and post-reperfusion biopsies, and the establishment of podocyte liquid biopsies/assays allow for the development of clinically relevant studies of podocyte biology. This has given insight into new pathways, involving novel targets in innate and adaptive immunity, such as SMPDL3b, cGAS-STING, and B7-1. Elegant experimental studies suggest that the successful clinical use of rituximab and abatacept, two immunomodulating agents, in our case series, may be due to direct effects on the podocyte, in addition to, or perhaps distinct from their immunosuppressive functions. Thus, tissue biomarker-directed therapy may provide a rational approach to validate the mechanism of disease and allow for the development of new therapeutics for FSGS. This report highlights recent progress in the field and emphasizes the importance of kidney transplantation and recurrent FSGS (rFSGS) as a platform for the study of primary FSGS.
Topics: Humans; Podocytes; Glomerulosclerosis, Focal Segmental; Kidney Glomerulus; Nephrotic Syndrome; Adaptive Immunity
PubMed: 37564655
DOI: 10.3389/fimmu.2023.1201619 -
Kidney International Nov 2022Podocytes undergo defined morphologic changes during development, homeostasis, and aging, and on injury. Quantitative podometric assessments of podocyte endowment...
Podocytes undergo defined morphologic changes during development, homeostasis, and aging, and on injury. Quantitative podometric assessments of podocyte endowment provide a powerful tool to interrogate glomerular health. Expanding this approach to a regional assessment demonstrates that the podocytes from cortical, subcortical, and juxtamedullary glomeruli are not only morphologically heterogeneous per se, but respond differently to stressors, such as age and hypertension. This suggests that zonal glomerular changes harbor critical information to understand glomerulopathies.
Topics: Humans; Podocytes; Kidney Glomerulus; Kidney Diseases; Hypertension
PubMed: 36272754
DOI: 10.1016/j.kint.2022.08.030 -
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 -
Kidney International Nov 2019The glomerular podocyte is one of the major targets of kidney research. Recent establishment of kidney organoids from pluripotent stem cells has enabled the detailed... (Review)
Review
The glomerular podocyte is one of the major targets of kidney research. Recent establishment of kidney organoids from pluripotent stem cells has enabled the detailed analysis of human podocytes in both development and disease. The podocytes in organoids express slit diaphragm-related genes and proteins and exhibit characteristic morphology, especially upon experimental transplantation. Organoid technology is now used to reproduce hereditary podocyte diseases, and selective podocyte induction methods have also been reported. Moreover, single-cell RNA-sequencing of human fetal and adult kidneys has revealed the detailed molecular features of this cell lineage, as well as serving as references for kidney organoids in which podocytes are still immature. Here, we discuss the recent progress and limitations of podocyte research from the viewpoint of developmental biology and kidney organoids.
Topics: Animals; Humans; Induced Pluripotent Stem Cells; Organoids; Podocytes; Stem Cell Research
PubMed: 31420196
DOI: 10.1016/j.kint.2019.04.044 -
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