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Current Medicinal Chemistry 2008Recent advances have identified the podocyte as a key target in glomerular injury. The podocyte is a highly specialized cell which is responsible for the glomerular... (Review)
Review
Recent advances have identified the podocyte as a key target in glomerular injury. The podocyte is a highly specialized cell which is responsible for the glomerular permselectivity for proteins in the kidney. Podocyte injury or loss leads to proteinuria. Apoptosis has been shown to contribute to renal cell loss, including loss of podocytes. The most striking feature of the podocyte is its ability to form intricate specialized cell junctions, the slit diaphragm. Slit diaphragm proteins play an important role in podocyte biology, protein permselectivity, cell signalling and disease. This review focuses on recent advances on the understanding of podocyte survival regulation, its relationship to slit diaphragm structure and function, and how this knowledge may affect our therapeutic approach to proteinuric kidney disease.
Topics: Animals; Cell Death; Disease Susceptibility; Humans; Kidney Diseases; Pharmaceutical Preparations; Podocytes
PubMed: 18673230
DOI: 10.2174/092986708784911542 -
Cells May 2024Podocyte health is vital for maintaining proper glomerular filtration in the kidney. Interdigitating foot processes from podocytes form slit diaphragms which regulate... (Review)
Review
Podocyte health is vital for maintaining proper glomerular filtration in the kidney. Interdigitating foot processes from podocytes form slit diaphragms which regulate the filtration of molecules through size and charge selectivity. The abundance of lipid rafts, which are ordered membrane domains rich in cholesterol and sphingolipids, near the slit diaphragm highlights the importance of lipid metabolism in podocyte health. Emerging research shows the importance of sphingolipid metabolism to podocyte health through structural and signaling roles. Dysregulation in sphingolipid metabolism has been shown to cause podocyte injury and drive glomerular disease progression. In this review, we discuss the structure and metabolism of sphingolipids, as well as their role in proper podocyte function and how alterations in sphingolipid metabolism contributes to podocyte injury and drives glomerular disease progression.
Topics: Podocytes; Sphingolipids; Humans; Animals; Lipid Metabolism; Kidney Diseases; Membrane Microdomains
PubMed: 38891023
DOI: 10.3390/cells13110890 -
Nature Reviews. Nephrology Mar 2019
Topics: Podocytes
PubMed: 30542151
DOI: 10.1038/s41581-018-0100-9 -
Nature Reviews. Nephrology Jun 2013In the past decade, our understanding of the role of podocytes in the function of the glomerular filtration barrier, and of the role of podocyte injury in the... (Review)
Review
In the past decade, our understanding of the role of podocytes in the function of the glomerular filtration barrier, and of the role of podocyte injury in the pathogenesis of proteinuric kidney disease, has substantially increased. Landmark genetic studies identified mutations in genes expressed by podocytes as a cause of albuminuria and nephrotic syndrome, leading to breakthrough discoveries from many laboratories. These discoveries contributed to a dramatic change in our view of the glomerular filtration barrier of the kidney and of the role of podocyte injury in the development of albuminuria and progressive kidney disease. In the past several years, studies have demonstrated that podocyte injury is a major cause of marked albuminuria and nephrotic syndrome, and have confirmed that podocytes are important for the maintenance of an intact glomerular filtration barrier. An essential role of loss of these cells in the pathogenesis of glomerulosclerosis and progressive proteinuric kidney disease has also been identified. In this Review, we discuss the importance of podocytes for the maintenance of an intact glomerular filtration barrier and their role in albumin handling.
Topics: Albuminuria; Animals; Glomerular Filtration Barrier; Humans; Podocytes; Serum Albumin
PubMed: 23609563
DOI: 10.1038/nrneph.2013.78 -
Advances in Chronic Kidney Disease Mar 2012During the past 2 decades, progress has been made in understanding the biology and mechanisms of podocyte injury and the relationship of these processes to... (Review)
Review
During the past 2 decades, progress has been made in understanding the biology and mechanisms of podocyte injury and the relationship of these processes to glomerulosclerosis. In addition, studies of human biopsies and animal models have provided insights into the mechanisms of glomerular disease progression and repair. These new developments are critical for establishing better therapeutic guidelines that target specific pathways, which otherwise would lead to irreversible injury.
Topics: Animals; Cellular Senescence; Disease Progression; Female; Glomerulosclerosis, Focal Segmental; Humans; Kidney Glomerulus; Male; Mice; Podocytes; Rats
PubMed: 22449344
DOI: 10.1053/j.ackd.2012.02.018 -
Pediatric Nephrology (Berlin, Germany) Mar 2016Several of the drugs currently used for the treatment of glomerular diseases are prescribed for their immunotherapeutic or anti-inflammatory properties, based on the... (Review)
Review
Several of the drugs currently used for the treatment of glomerular diseases are prescribed for their immunotherapeutic or anti-inflammatory properties, based on the current understanding that glomerular diseases are mediated by immune responses. In recent years our understanding of podocytic signalling pathways and the crucial role of genetic predispositions in the pathology of glomerular diseases has broadened. Delineation of those signalling pathways supports the hypothesis that several of the medications and immunosuppressive agents used to treat glomerular diseases directly target glomerular podocytes. Several central downstream signalling pathways merge into regulatory pathways of the podocytic actin cytoskeleton and its connection to the slit diaphragm. The slit diaphragm and the cytoskeleton of the foot process represent a functional unit. A breakdown of the cytoskeletal backbone of the foot processes leads to internalization of slit diaphragm molecules, and internalization of slit diaphragm components in turn negatively affects cytoskeletal signalling pathways. Podocytes display a remarkable ability to recover from complete effacement and to re-form interdigitating foot processes and intact slit diaphragms after pharmacological intervention. This ability indicates an active inside-out signalling machinery which stabilizes integrin complex formations and triggers the recycling of slit diaphragm molecules from intracellular compartments to the cell surface. In this review we summarize current evidence from patient studies and model organisms on the direct impact of immunosuppressive and supportive drugs on podocyte signalling pathways. We highlight new therapeutic targets that may open novel opportunities to enhance and stabilize inside-out pathways in podocytes.
Topics: Animals; Cytoskeleton; Drug Discovery; Humans; Molecular Targeted Therapy; Nephrotic Syndrome; Podocytes; Renal Agents; Signal Transduction
PubMed: 25939817
DOI: 10.1007/s00467-015-3116-4 -
Methods in Molecular Biology (Clifton,... 2020Vertebrate podocytes are kidney glomerular cells critically required for normal renal filtration. To fulfill their role, podocytes form molecular sieves known as slit...
Vertebrate podocytes are kidney glomerular cells critically required for normal renal filtration. To fulfill their role, podocytes form molecular sieves known as slit diaphragms that contribute to the glomerular filtration barrier. The disruption of podocyte biology or slit diaphragm formation in humans is a precursor to albuminuria, renal failure, and cardiovascular morbidity. Due to genetic and functional similarities, the nephrocytes of Drosophila are increasingly used to model the genetic and metabolic basis of human podocyte biology. They have the advantage that they are a much quicker system to study compared to other murine transgenic models. In this chapter we present methods to modulate and study Drosophila nephrocyte function and diaphragm formation.
Topics: Animals; Animals, Genetically Modified; Cell Culture Techniques; Cell Membrane; DNA-Binding Proteins; Disease Models, Animal; Drosophila melanogaster; Gene Expression Regulation; Genetic Engineering; Humans; Kidney Diseases; Kruppel-Like Transcription Factors; Membrane Proteins; Nuclear Proteins; Optical Imaging; Podocytes; Saccharomyces cerevisiae Proteins; Transcription Factors
PubMed: 31701442
DOI: 10.1007/978-1-4939-9841-8_2 -
Nature Reviews. Nephrology Jul 2021
Topics: Calcium; Calcium Signaling; Humans; Morphogenesis; Podocytes
PubMed: 34002065
DOI: 10.1038/s41581-021-00445-z -
Nature Reviews. Nephrology Oct 2011Almost all mammalian cell types have morphologies that are uniquely tailored to their physiological functions. This immense variation in cell shape depends on an... (Review)
Review
Almost all mammalian cell types have morphologies that are uniquely tailored to their physiological functions. This immense variation in cell shape depends on an underlying network of dynamic and interconnected actin and microtubule polymers. The glomerular podocyte is an archetypal example of such specialization, with a complex cytoskeleton underlying its delicate architectural features. Dynamic control of this cytoskeletal matrix seems to center around the slit diaphragm, a complex of proteins at the cell-cell junction between adjacent podocyte foot processes. This junction includes molecules that are unique to the podocyte that probably determine the correct morphology of the cell, and are targets of disease processes that disrupt the intricate balance of signaling that controls the cytoskeletal matrix. This Review will outline the most recent concepts and advances in our understanding of this critical aspect of glomerular biology, as well as discussing how an improved understanding of the podocyte cytoskeleton is starting to shape advances in delineating the pathogenesis of common glomerular diseases.
Topics: Cytoskeleton; Humans; Kidney Diseases; Podocytes
PubMed: 22025085
DOI: 10.1038/nrneph.2011.151 -
Metabolism: Clinical and Experimental Jan 2024Podocyte injury is considered as the most important early event contributing to diabetic kidney disease (DKD). Recent findings provide new insights into the roles of...
BACKGROUND AND AIMS
Podocyte injury is considered as the most important early event contributing to diabetic kidney disease (DKD). Recent findings provide new insights into the roles of lipids and lipid-modulating proteins as key determinants of podocyte function in health and kidney disease. CCDC92, a novel member of coiled-coil domain-containing protein family, was indicated relevant to lipid metabolism, coronary heart disease and type 2 diabetes. However, the expression pattern and role of CCDC92 in the kidney is not clear. This study was designed to elucidate the contribution of CCDC92 in the pathogenesis of DKD.
METHODS
Sections with a pathological diagnosis of different classes of DKD, including subjects with mild DKD (class II, n = 6), subjects with moderate DKD (class III, n = 6) or subjects with severe DKD (class IV, n = 6), and control samples (n = 12) were detected for the expression level of CCDC92 and lipid accumulation. Two types of diabetic mice model (db/db and HFD/STZ) in podocyte-specific Ccdc92 knockout background were generated to clarify the role of CCDC92 in podocyte lipotoxicity.
RESULTS
The level of CCDC92 was increased in renal biopsies sections from patients with DKD, which was correlated with eGFR and lipid accumulation in glomeruli. In animal studies, CCDC92 were also induced in the kidney from two independent diabetic models, especially in podocytes. Podocyte-specific deletion of Ccdc92 ameliorated podocyte injury and ectopic lipid deposition under diabetic condition. Mechanically, CCDC92 promoted podocyte lipotoxicity, at least in part through ABCA1 signaling-mediated lipid homeostasis.
CONCLUSION
Our studies demonstrates that CCDC92 acts as a novel regulator of lipid homeostasis to promote podocyte injury in DKD, suggesting that CCDC92 might be a potential biomarker of podocyte injury in DKD, and targeting CCDC92 may be an effective innovative therapeutic strategy for patients with DKD.
Topics: Animals; Humans; Mice; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Podocytes; Cytoskeletal Proteins; Lipid Metabolism
PubMed: 37952690
DOI: 10.1016/j.metabol.2023.155724