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Kidney International Jun 2016Podocytes maintain the glomerular filtration barrier, and the stability of this barrier depends on their highly differentiated postmitotic phenotype, which also defines... (Review)
Review
Podocytes maintain the glomerular filtration barrier, and the stability of this barrier depends on their highly differentiated postmitotic phenotype, which also defines the particular vulnerability of the glomerulus. Recent podocyte biology and gene disruption studies in vivo indicate a causal relationship between abnormalities of single podocyte molecules and proteinuria and glomerulosclerosis. Podocytes live under various stresses and pathological stimuli. They adapt to maintain homeostasis, but excessive stress leads to maladaptation with complex biological changes including loss of integrity and dysregulation of cellular metabolism. Podocyte injury causes proteinuria and detachment from the glomerular basement membrane. In addition to "sick" podocytes and their detachment, our understanding of glomerular responses following podocyte loss needs to address the pathways from podocyte injury to sclerosis. Studies have found a variety of glomerular responses to podocyte dysfunction in vivo, such as disruption of podocyte-endothelial cross talk and activation of podocyte-parietal cell interactions, all of which help us to understand the complex scenario of podocyte injury and its consequences. This review focuses on the cellular aspects of podocyte dysfunction and the adaptive or maladaptive glomerular responses to podocyte injury that lead to its major consequence, glomerulosclerosis.
Topics: Apoptosis; Bowman Capsule; Cell Communication; Cell Differentiation; Endothelial Cells; Glomerular Basement Membrane; Glomerulosclerosis, Focal Segmental; Humans; Oxidative Stress; Podocytes; Proteinuria; Sclerosis; Stress, Mechanical
PubMed: 27165817
DOI: 10.1016/j.kint.2016.01.012 -
American Journal of Nephrology 2018Podocyte biology is a developing science that promises to help improve understanding of the mechanistic nature of multiple diseases associated with proteinuria.... (Review)
Review
BACKGROUND
Podocyte biology is a developing science that promises to help improve understanding of the mechanistic nature of multiple diseases associated with proteinuria. Proteinuria in nephrotic syndrome has been linked to mechanistic dysfunctions in the renal glomerulus involving the function of podocyte epithelial cells, including podocyte foot process effacement.
SUMMARY
Developments in imaging technology are improving knowledge of the detailed structure of the human renal glomerulus and cortex. Podocyte foot processes attach themselves to the glomerular capillaries at the glomerular basement membrane (GBM) forming intercellular junctions that form slit diaphragm filtration barriers that help maintain normal renal function. Damage in this area has been implicated in glomerular disease. Injured podocytes undergo effacement whereby they lose their structure and spread out, leading to a reduction in filtration barrier function. Effacement is typically associated with the presence of proteinuria in focal segmental glomerulosclerosis, minimal change disease, and diabetes. It is thought to be due to a breakdown in the actin cytoskeleton of the foot processes, complex contractile apparatuses that allow podocytes to dynamically reorganize according to changes in filtration requirements. The process of podocyte depletion correlates with the development of glomerular sclerosis and chronic kidney disease. Focal adhesion complexes that interact with the underlying GBM bind the podocytes within the glomerular structure and prevent their detachment. Key Messages: Knowledge of glomerular podocyte biology is helping to advance our understanding of the science and mechanics of the glomerular filtering process, opening the way to a variety of new potential applications for clinical targeting.
Topics: Actins; Humans; Membrane Proteins; Nephrotic Syndrome; Podocytes; Proteinuria
PubMed: 29852492
DOI: 10.1159/000481633 -
Cell Metabolism Dec 2020Lipid accumulation in podocytes is a major determinant of diabetic kidney disease (DKD) and identification of potential therapeutic targets by mediating podocyte lipid...
Lipid accumulation in podocytes is a major determinant of diabetic kidney disease (DKD) and identification of potential therapeutic targets by mediating podocyte lipid metabolism has clinical importance. This study was to elucidate the role of JAML (junctional adhesion molecule-like protein) in the pathogenesis of DKD. We first confirmed the expression of JAML in podocytes and found that podocyte-specific deletion of Jaml ameliorated podocyte injury and proteinuria in two different models of diabetic mice. We further demonstrated a novel role of JAML in regulating podocyte lipid metabolism through SIRT1-mediated SREBP1 signaling. Similar results were also found in mice with adriamycin-induced nephropathy. Importantly, we observed a higher expression of JAML in glomeruli from subjects with DKD and other types of proteinuric kidney diseases, and the level of JAML was correlated with lipid accumulation and glomerular filtration rate, suggesting that JAML may be an attractive therapeutic target for proteinuric kidney disease.
Topics: Adult; Aged; Animals; Cell Adhesion Molecules; Cell Line; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Female; Humans; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Middle Aged; Podocytes; Rats; Young Adult
PubMed: 33186558
DOI: 10.1016/j.cmet.2020.10.019 -
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 -
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 -
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 -
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 -
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 -
Nephron. Experimental Nephrology 2006Cytoskeletal dynamics play important roles during normal podocyte development, in maintenance of the healthy glomerular filter, and in glomerular pathology. During the... (Review)
Review
Cytoskeletal dynamics play important roles during normal podocyte development, in maintenance of the healthy glomerular filter, and in glomerular pathology. During the past few years, essential progress has been made in understanding the molecular mechanisms that govern podocyte cytoskeletal dynamics, nevertheless this knowledge remains incomplete. Examination of the podocyte cytoskeleton presents unique challenges to the experimentalist who is faced with attempting to model a morphologically complex cell that is situated in a complex microenvironment. This review will summarize recent progress in understanding cytoskeletal dynamics in the podocyte and will review modern imaging techniques relevant to studying this area of podocyte biology.
Topics: Actins; Animals; Diagnostic Imaging; Humans; Mitochondria; Podocytes
PubMed: 16543767
DOI: 10.1159/000090619 -
American Journal of Physiology. Renal... Dec 2018Proteases regulate glomerular physiology. The last decade has revealed a multitude of podocyte proteases that govern the glomerular response to numerous chemical,... (Review)
Review
Proteases regulate glomerular physiology. The last decade has revealed a multitude of podocyte proteases that govern the glomerular response to numerous chemical, mechanical, and metabolic cues. These proteases form a protein signaling web that integrates stress stimuli and serves as a key controller of the glomerular microenvironment. Both the extracellular and intracellular proteolytic networks are perturbed in focal segmental glomerulosclerosis, as well as hypertensive and diabetic nephropathy. Accordingly, the highly intertwined podocyte protease web is an integrative part of the podocyte's damage response. Novel mass spectrometry-based technologies will help to untangle this proteolytic network: functional readouts acquired from deep podocyte proteomics, single glomerular proteomics, and degradomics have exposed unanticipated protease activity in podocytes. Future efforts should characterize the interdependency and upstream regulation of key proteases, along with their role in promoting tissue heterogeneity in glomerular diseases. These efforts will not only illuminate the machinery of podocyte proteostasis but also reveal avenues for therapeutic intervention in the podocyte protease web.
Topics: Animals; Cellular Microenvironment; Extracellular Matrix; Fibrosis; Humans; Kidney Diseases; Kidney Glomerulus; Peptide Hydrolases; Podocytes; Proteostasis; Signal Transduction
PubMed: 30230368
DOI: 10.1152/ajprenal.00380.2018