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Journal of the American Society of... Mar 2023The loss of integrity of the glomerular filtration barrier results in proteinuria that is often attributed to podocyte loss. Yet how damaged podocytes are lost remains...
SIGNIFICANCE STATEMENT
The loss of integrity of the glomerular filtration barrier results in proteinuria that is often attributed to podocyte loss. Yet how damaged podocytes are lost remains unknown. Germline loss of murine podocyte-associated Hdac1 and Hdac2 ( Hdac1/2 ) results in proteinuria and collapsing glomerulopathy due to sustained double-stranded DNA damage. Hdac1/2 deletion induces loss of podocyte quiescence, cell cycle entry, arrest in G1, and podocyte senescence, observed both in vivo and in vitro . Through the senescence secretory associated phenotype, podocytes secrete proteins that contribute to their detachment. These results solidify the role of HDACs in cell cycle regulation and senescence, providing important clues in our understanding of how podocytes are lost following injury.
BACKGROUND
Intact expression of podocyte histone deacetylases (HDAC) during development is essential for maintaining a normal glomerular filtration barrier because of its role in modulating DNA damage and preventing premature senescence.
METHODS
Germline podocyte-specific Hdac1 and 2 ( Hdac1 / 2 ) double-knockout mice were generated to examine the importance of these enzymes during development.
RESULTS
Podocyte-specific loss of Hdac1 / 2 in mice resulted in severe proteinuria, kidney failure, and collapsing glomerulopathy. Hdac1 / 2 -deprived podocytes exhibited classic characteristics of senescence, such as senescence-associated β-galactosidase activity and lipofuscin aggregates. In addition, DNA damage, likely caused by epigenetic alterations such as open chromatin conformation, not only resulted in podocyte cell-cycle entry as shown in vivo by Ki67 expression and by FUCCI-2aR mice, but also in p21-mediated cell-cycle arrest. Through the senescence secretory associated phenotype, the damaged podocytes secreted proinflammatory cytokines, growth factors, and matrix metalloproteinases, resulting in subsequent podocyte detachment and loss, evidenced by senescent podocytes in urine.
CONCLUSIONS
Hdac1 / 2 plays an essential role during development. Loss of these genes in double knockout mice leads to sustained DNA damage and podocyte senescence and loss.
Topics: Animals; Mice; Cell Cycle; Histone Deacetylase 1; Mice, Knockout; Podocytes; Proteinuria
PubMed: 36414418
DOI: 10.1681/ASN.2022050598 -
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 -
Kidney International Mar 2009Recent insights have defined the central role of podocytes both in rare genetic diseases and as a general determinant of the progression of human glomerular diseases. In...
Recent insights have defined the central role of podocytes both in rare genetic diseases and as a general determinant of the progression of human glomerular diseases. In a recent issue of Nature, Weavers et al. described a podocyte-like cell type in Drosophila, the nephrocyte, that closely resembles mammalian podocytes, including the nephrin-based slit diaphragm. This novel podocyte system might open new avenues toward the understanding of podocyte biology and pathophysiology.
Topics: Animals; Basement Membrane; Drosophila melanogaster; Humans; Membrane Proteins; Podocytes; Signal Transduction
PubMed: 19219000
DOI: 10.1038/ki.2008.653 -
Biomolecules May 2022Nitric oxide (NO) is a potent signaling molecule involved in many physiological and pathophysiological processes in the kidney. NO plays a complex role in glomerular... (Review)
Review
Nitric oxide (NO) is a potent signaling molecule involved in many physiological and pathophysiological processes in the kidney. NO plays a complex role in glomerular ultrafiltration, vasodilation, and inflammation. Changes in NO bioavailability in pathophysiological conditions such as hypertension or diabetes may lead to podocyte damage, proteinuria, and rapid development of chronic kidney disease (CKD). Despite the extensive data highlighting essential functions of NO in health and pathology, related signaling in glomerular cells, particularly podocytes, is understudied. Several reports indicate that NO bioavailability in glomerular cells is decreased during the development of renal pathology, while restoring NO level can be beneficial for glomerular function. At the same time, the compromised activity of nitric oxide synthase (NOS) may provoke the formation of peroxynitrite and has been linked to autoimmune diseases such as systemic lupus erythematosus. It is known that the changes in the distribution of NO sources due to shifts in NOS subunits expression or modifications of NADPH oxidases activity may be linked to or promote the development of pathology. However, there is a lack of information about the detailed mechanisms describing the production and release of NO in the glomerular cells. The interaction of NO and other reactive oxygen species in podocytes and how NO-calcium crosstalk regulates glomerular cells' function is still largely unknown. Here, we discuss recent reports describing signaling, synthesis, and known pathophysiological mechanisms mediated by the changes in NO homeostasis in the podocyte. The understanding and further investigation of these essential mechanisms in glomerular cells will facilitate the design of novel strategies to prevent or manage health conditions that cause glomerular and kidney damage.
Topics: Humans; Kidney; Kidney Glomerulus; Nitric Oxide; Nitric Oxide Synthase; Podocytes; Proteinuria
PubMed: 35740870
DOI: 10.3390/biom12060745 -
Advances in Experimental Medicine and... 2019Finding new therapeutic targets of glomerulosclerosis treatment is an ongoing quest. Due to a living environment of various stresses and pathological stimuli, podocytes... (Review)
Review
Finding new therapeutic targets of glomerulosclerosis treatment is an ongoing quest. Due to a living environment of various stresses and pathological stimuli, podocytes are prone to injuries; moreover, as a cell without proliferative potential, loss of podocytes is vital in the pathogenesis of glomerulosclerosis. Thus, sufficient understanding of factors and underlying mechanisms of podocyte injury facilitates the advancement of treating and prevention of glomerulosclerosis. The clinical symptom of podocyte injury is proteinuria, sometimes with loss of kidney functions progressing to glomerulosclerosis. Injury-induced changes in podocyte physiology and function are actually not a simple passive process, but a complex interaction of proteins that comprise the anatomical structure of podocytes at molecular levels. This chapter lists several aspects of podocyte injuries along with potential mechanisms, including glucose and lipid metabolism disorder, hypertension, RAS activation, micro-inflammation, immune disorder, and other factors. These aspects are not technically separated items, but intertwined with each other in the pathogenesis of podocyte injuries.
Topics: Glomerulosclerosis, Focal Segmental; Humans; Hypertension; Inflammation; Lipid Metabolism Disorders; Podocytes; Proteinuria
PubMed: 31399967
DOI: 10.1007/978-981-13-8871-2_10 -
Seminars in Nephrology Jul 2014The very limited ability of adult podocytes to proliferate in vivo is clinically significant because podocytes form a vascular barrier that is functionally critical to... (Review)
Review
The very limited ability of adult podocytes to proliferate in vivo is clinically significant because podocytes form a vascular barrier that is functionally critical to the nephron, podocyte hypoplasia is a characteristic of disease, and inadequate regeneration of podocytes is a major cause of persistent podocyte hypoplasia. Excessive podocyte loss or inadequate replacement leads to glomerulosclerosis in many progressive kidney diseases. Thus, restoration of podocyte cell density almost certainly is reliant on regeneration by podocyte progenitors. However, such putative progenitors have remained elusive until recently. In this review, we describe the developmental processes leading to podocyte and parietal epithelial cell (PEC) formation during glomerulogenesis. We compare evidence that in normal human kidneys PECs expressing progenitor markers CD133 and CD24 can differentiate into podocytes in vitro and in vivo, with evidence from animal models suggesting a more limited role of the PEC's capacity to serve as a podocyte progenitor in adults. We highlight tantalizing new evidence that specialized vascular wall cells of afferent arterioles, including those that produce renin in healthy kidney, provide a novel local progenitor source of new PECs and podocytes in response to podocyte hypoplasia in the adult, and draw comparisons with glomerulogenesis.
Topics: Epithelial Cells; Humans; Kidney; Kidney Glomerulus; Podocytes; Regeneration; Stem Cells
PubMed: 25217270
DOI: 10.1016/j.semnephrol.2014.06.008 -
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 -
Biomolecular Concepts Aug 2014Podocytes are postmitotic renal glomerular cells with multiple ramifications that extend from the cell body. Processes departing from a podocyte interdigitate with... (Review)
Review
Podocytes are postmitotic renal glomerular cells with multiple ramifications that extend from the cell body. Processes departing from a podocyte interdigitate with corresponding projections from neighboring cells and form an intricate web that enwraps the glomerular capillary completely. Podocyte processes are interconnected by the slit diaphragm, an adhesion junction mostly formed by Ig-like molecules, cadherins/protocadherins, ephrin/eph, and neurexin molecules organized in an assembly that resembles synaptic junctions. Podocyte failure is primarily or secondarily implicated in all forms of proteinuric glomerular diseases, as confirmed by the morphological changes of their elaborate cell architecture detectable by electron microscopy. Importantly, mutations of podocyte proteins are responsible for the most severe forms of congenital nephrotic syndrome. In the last 15 years, progressive technological advances have aided the study of podocyte biology and pathology, confirming the relevance of podocyte molecules and signaling pathways for the function of the glomerular filter. This review will examine the most important and newest discoveries in the field, which is rapidly evolving, hopefully leading to a detailed knowledge of this fascinating cell and to the development of specific therapeutic options for proteinuric diseases.
Topics: Animals; Humans; Kidney Diseases; Kidney Glomerulus; Membrane Proteins; Mice; Models, Biological; Podocytes; Proteinuria; Signal Transduction
PubMed: 25372762
DOI: 10.1515/bmc-2014-0020 -
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 -
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