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Pharmacology & Therapeutics Aug 2023Vitamin A (VA, retinol) and its metabolites (commonly called retinoids) are required for the proper development of the kidney during embryogenesis, but retinoids also... (Review)
Review
Vitamin A (VA, retinol) and its metabolites (commonly called retinoids) are required for the proper development of the kidney during embryogenesis, but retinoids also play key roles in the function and repair of the kidney in adults. Kidneys filter 180-200 liters of blood per day and each kidney contains approximately 1 million nephrons, which are often referred to as the 'functional units' of the kidney. Each nephron consists of a glomerulus and a series of tubules (proximal tubule, loop of Henle, distal tubule, and collecting duct) surrounded by a network of capillaries. VA is stored in the liver and converted to active metabolites, most notably retinoic acid (RA), which acts as an agonist for the retinoic acid receptors ((RARs α, β, and γ) to regulate gene transcription. In this review we discuss some of the actions of retinoids in the kidney after injury. For example, in an ischemia-reperfusion model in mice, injury-associated loss of proximal tubule (PT) differentiation markers occurs, followed by re-expression of these differentiation markers during PT repair. Notably, healthy proximal tubules express ALDH1a2, the enzyme that metabolizes retinaldehyde to RA, but transiently lose ALDH1a2 expression after injury, while nearby myofibroblasts transiently acquire RA-producing capabilities after injury. These results indicate that RA is important for renal tubular injury repair and that compensatory mechanisms exist for the generation of endogenous RA by other cell types upon proximal tubule injury. ALDH1a2 levels also increase in podocytes, epithelial cells of the glomeruli, after injury, and RA promotes podocyte differentiation. We also review the ability of exogenous, pharmacological doses of RA and receptor selective retinoids to treat numerous kidney diseases, including kidney cancer and diabetic kidney disease, and the emerging genetic evidence for the importance of retinoids and their receptors in maintaining or restoring kidney function after injury. In general, RA has a protective effect on the kidney after various types of injuries (eg. ischemia, cytotoxic actions of chemicals, hyperglycemia related to diabetes). As more research into the actions of each of the three RARs in the kidney is carried out, a greater understanding of the actions of vitamin A is likely to lead to new insights into the pathology of kidney disorders and the development of new therapies for kidney diseases.
Topics: Vitamin A; Kidney; Retinoids; Receptors, Retinoic Acid; Tretinoin; Kidney Diseases
PubMed: 37331524
DOI: 10.1016/j.pharmthera.2023.108481 -
Journal of Nephrology Dec 2023Acute kidney injury development after trauma, burn, or sepsis occurs frequently but remains a scientific and clinical challenge. Whereas the pathophysiological focus has... (Review)
Review
Acute kidney injury development after trauma, burn, or sepsis occurs frequently but remains a scientific and clinical challenge. Whereas the pathophysiological focus has mainly been on hemodynamics and the downstream renal tubular system, little is known about alterations upstream within the glomerulus post trauma or during sepsis. Particularly for the glomerular endothelial cells, mesangial cells, basal membrane, and podocytes, all of which form the glomerular filter, there are numerous in vitro studies on the molecular and functional consequences upon exposure of single cell types to specific damage- or microbial-associated molecular patterns. By contrast, a lack of knowledge exists in the real world regarding the orchestrated inflammatory response of the glomerulus post trauma or burn or during sepsis. Therefore, we aim to provide an overview on the glomerulus as an immune target but also as a perpetrator of the danger response to traumatic and septic conditions, and present major players involved in the context of critical illness. Finally, we highlight research gaps of this rather neglected but worthwhile area to define future molecular targets and therapeutic strategies to prevent or improve the course of AKI after trauma, burn, or sepsis.
Topics: Humans; Endothelial Cells; Kidney Glomerulus; Burns; Acute Kidney Injury; Sepsis
PubMed: 37542608
DOI: 10.1007/s40620-023-01718-5 -
JCI Insight Oct 2023Albuminuria and podocyte injury are the key cellular events in the progression of diabetic nephropathy (DN). Acetyl-CoA synthetase 2 (ACSS2) is a nucleocytosolic enzyme...
Albuminuria and podocyte injury are the key cellular events in the progression of diabetic nephropathy (DN). Acetyl-CoA synthetase 2 (ACSS2) is a nucleocytosolic enzyme responsible for the regulation of metabolic homeostasis in mammalian cells. This study aimed to investigate the possible roles of ACSS2 in kidney injury in DN. We constructed an ACSS2-deleted mouse model to investigate the role of ACSS2 in podocyte dysfunction and kidney injury in diabetic mouse models. In vitro, podocytes were chosen and transfected with ACSS2 siRNA and ACSS2 inhibitor and treated with high glucose. We found that ACSS2 expression was significantly elevated in the podocytes of patients with DN and diabetic mice. ACSS2 upregulation promoted phenotype transformation and inflammatory cytokine expression while inhibiting podocytes' autophagy. Conversely, ACSS2 inhibition improved autophagy and alleviated podocyte injury. Furthermore, ACSS2 epigenetically activated raptor expression by histone H3K9 acetylation, promoting activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Pharmacological inhibition or genetic depletion of ACSS2 in the streptozotocin-induced diabetic mouse model greatly ameliorated kidney injury and podocyte dysfunction. To conclude, ACSS2 activation promoted podocyte injury in DN by raptor/mTORC1-mediated autophagy inhibition.
Topics: Animals; Humans; Mice; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; Kidney; Ligases; Mammals; Mechanistic Target of Rapamycin Complex 1; Acetate-CoA Ligase
PubMed: 37870960
DOI: 10.1172/jci.insight.165817 -
Nature Reviews. Nephrology May 2024Podocytes are the key target cells for injury across the spectrum of primary and secondary proteinuric kidney disorders, which account for up to 90% of cases of kidney... (Review)
Review
Podocytes are the key target cells for injury across the spectrum of primary and secondary proteinuric kidney disorders, which account for up to 90% of cases of kidney failure worldwide. Seminal experimental and clinical studies have established a causative link between podocyte depletion and the magnitude of proteinuria in progressive glomerular disease. However, no substantial advances have been made in glomerular disease therapies, and the standard of care for podocytopathies relies on repurposed immunosuppressive drugs. The past two decades have seen a remarkable expansion in understanding of the mechanistic basis of podocyte injury, with prospects increasing for precision-based treatment approaches. Dozens of disease-causing genes with roles in the pathogenesis of clinical podocytopathies have been identified, as well as a number of putative glomerular permeability factors. These achievements, together with the identification of novel targets of podocyte injury, the development of potential approaches to harness the endogenous podocyte regenerative potential of progenitor cell populations, ongoing clinical trials of podocyte-specific pharmacological agents and the development of podocyte-directed drug delivery systems, contribute to an optimistic outlook for the future of glomerular disease therapy.
PubMed: 38724717
DOI: 10.1038/s41581-024-00843-z -
International Journal of Molecular... Jan 2024Podocyte injury can disrupt the glomerular filtration barrier (GFB), leading to podocytopathies that emphasize podocytes as the glomerulus's key organizer. The... (Review)
Review
Podocyte injury can disrupt the glomerular filtration barrier (GFB), leading to podocytopathies that emphasize podocytes as the glomerulus's key organizer. The coordinated cytoskeleton is essential for supporting the elegant structure and complete functions of podocytes. Therefore, cytoskeleton rearrangement is closely related to the pathogenesis of podocytopathies. In podocytopathies, the rearrangement of the cytoskeleton refers to significant alterations in a string of slit diaphragm (SD) and focal adhesion proteins such as the signaling node nephrin, calcium influx via transient receptor potential channel 6 (TRPC6), and regulation of the Rho family, eventually leading to the disorganization of the original cytoskeletal architecture. Thus, it is imperative to focus on these proteins and signaling pathways to probe the cytoskeleton rearrangement in podocytopathies. In this review, we describe podocytopathies and the podocyte cytoskeleton, then discuss the molecular mechanisms involved in cytoskeleton rearrangement in podocytopathies and summarize the effects of currently existing drugs on regulating the podocyte cytoskeleton.
Topics: Cytoskeleton; Microtubules; Calcium, Dietary; Focal Adhesions; Glomerular Filtration Barrier
PubMed: 38203817
DOI: 10.3390/ijms25010647 -
Molecular Therapy : the Journal of the... Nov 2023Focal segmental glomerulosclerosis (FSGS) is the most common glomerular disorder causing end-stage renal diseases worldwide. Central to the pathogenesis of FSGS is...
Focal segmental glomerulosclerosis (FSGS) is the most common glomerular disorder causing end-stage renal diseases worldwide. Central to the pathogenesis of FSGS is podocyte dysfunction, which is induced by diverse insults. However, the mechanism governing podocyte injury and repair remains largely unexplored. Asparagine endopeptidase (AEP), a lysosomal protease, regulates substrates by residue-specific cleavage or degradation. We identified the increased AEP expression in the primary proteinuria model which was induced by adriamycin (ADR) to mimic human FSGS. In vivo, global AEP knockout mice manifested increased injury-susceptibility of podocytes in ADR-induced nephropathy (ADRN). Podocyte-specific AEP knockout mice exhibited much more severe glomerular lesions and podocyte injury after ADR injection. In contrast, podocyte-specific augmentation of AEP in mice protected against ADRN. In vitro, knockdown and overexpression of AEP in human podocytes revealed the cytoprotection of AEP as a cytoskeleton regulator. Furthermore, transgelin, an actin-binding protein regulating actin dynamics, was cleaved by AEP, and, as a result, removed its actin-binding regulatory domain. The truncated transgelin regulated podocyte actin dynamics and repressed podocyte hypermotility, compared to the native full-length transgelin. Together, our data reveal a link between lysosomal protease AEP and podocyte cytoskeletal homeostasis, which suggests a potential therapeutic role for AEP in proteinuria disease.
Topics: Animals; Humans; Mice; Actins; Doxorubicin; Glomerulosclerosis, Focal Segmental; Kidney Diseases; Mice, Knockout; Microfilament Proteins; Podocytes; Proteinuria; Cysteine Endopeptidases
PubMed: 37689970
DOI: 10.1016/j.ymthe.2023.09.003 -
Kidney International Sep 2023The majority of podocyte disorders are progressive in nature leading to chronic kidney disease and often kidney failure. The scope of current therapies is typically... (Review)
Review
The majority of podocyte disorders are progressive in nature leading to chronic kidney disease and often kidney failure. The scope of current therapies is typically nonspecific immunosuppressant medications, which are accompanied by unwanted and serious side effects. However, many exciting clinical trials are underway to reduce the burden of podocyte diseases in our patients. Major advances and discoveries have recently been made experimentally in our understanding of the molecular and cellular mechanisms underlying podocyte injury in disease. This begs the question of how best to take advantage of these impressive strides. One approach to consider is the repurposing of therapeutics that have already been approved by the Food and Drug Administration, European Medicines Agency, and other regulatory agencies for indications beyond the kidney. The advantages of therapy repurposing include known safety profiles, drug development that has already been completed, and overall reduced costs for studying alternative indications for selected therapies. The purpose of this mini review is to examine the experimental literature of podocyte damage and determine if there are mechanistic targets in which prior approved therapies can be considered for repurposing to podocyte disorders.
Topics: Humans; Podocytes; Pharmaceutical Preparations; Drug Repositioning; Kidney; Renal Insufficiency, Chronic
PubMed: 37290603
DOI: 10.1016/j.kint.2023.05.018 -
Journal of Cellular Physiology Oct 2023Podocytes are terminally differentiated kidney cells acting as the main gatekeepers of the glomerular filtration barrier; hence, inhibiting proteinuria. Podocytopathies... (Review)
Review
Podocytes are terminally differentiated kidney cells acting as the main gatekeepers of the glomerular filtration barrier; hence, inhibiting proteinuria. Podocytopathies are classified as kidney diseases caused by podocyte damage. Different genetic and environmental risk factors can cause podocyte damage and death. Recent evidence shows that mitochondrial dysfunction also contributes to podocyte damage. Understanding alterations in mitochondrial metabolism and function in podocytopathies and whether altered mitochondrial homeostasis/dynamics is a cause or effect of podocyte damage are issues that need in-depth studies. This review highlights the roles of mitochondria and their bioenergetics in podocytes. Then, factors/signalings that regulate mitochondria in podocytes are discussed. After that, the role of mitochondrial dysfunction is reviewed in podocyte injury and the development of different podocytopathies. Finally, the mitochondrial therapeutic targets are considered.
PubMed: 37659096
DOI: 10.1002/jcp.31110 -
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 -
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