Abstract
Hypoxia-inducible factor1 (HIF1) plays a pivotal role in ensuring cells adapt to low-oxygen conditions. Depletion of oxygen, a co-substrate during hydroxylation of prolyl (P402 and P564) residues of HIF1⍺, evades HIF1⍺ ubiquitination and enables its dimerization with HIF1β to mediate global transcriptional response to hypoxia. Though HIF1 is largely considered eliciting a protective role during physiological or pathological hypoxia or ischemia, elevated HIF1 during chronic hypoxia contributes to glomerular diseases' pathology and proteinuria. The glomerulus is responsible for renal permselectivity and excretion of ultra-filtrated urine. Podocytes are the glomerulus' major cell types and are instrumental for glomerular filtration, permselectivity, and glomerular basement membrane maintenance. Podocyte injury is expected to impair the efficiency of glomerular filtration and manifestation of glomerulosclerosis and proteinuria. Accumulated evidence suggests that podocytes are susceptible to various insults during chronic hypoxia, including podocyte EMT, slit-diaphragm dysfunction, foot process effacement, and cytoskeletal derangement due to accumulation of HIF1. This review discusses how hypoxia/HIF1 signaling regulates various features and function of podocytes during exposure to chronic hypoxia or inducing HIF1 by various chemical modulators.
Keywords:
EMT; HIF; Hypoxia; Podocyte; Proteinuria; Slit-diaphragm.
MeSH terms
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Animals
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Aryl Hydrocarbon Receptor Nuclear Translocator / genetics*
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Aryl Hydrocarbon Receptor Nuclear Translocator / metabolism
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Chronic Disease
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Cytoskeleton / metabolism
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Cytoskeleton / pathology
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Epithelial-Mesenchymal Transition
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Gene Expression Regulation
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Glomerular Filtration Barrier / metabolism
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Glomerular Filtration Barrier / pathology
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Glomerulonephritis / etiology
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Glomerulonephritis / genetics*
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Glomerulonephritis / metabolism
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Glomerulonephritis / pathology
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Glomerulosclerosis, Focal Segmental / etiology
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Glomerulosclerosis, Focal Segmental / genetics*
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Glomerulosclerosis, Focal Segmental / metabolism
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Glomerulosclerosis, Focal Segmental / pathology
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Humans
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Hypoxia / complications
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Hypoxia / genetics*
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Hypoxia / metabolism
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Hypoxia / pathology
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Podocytes / metabolism*
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Podocytes / pathology
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Proteinuria / etiology
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Proteinuria / genetics*
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Proteinuria / metabolism
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Proteinuria / pathology
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Signal Transduction
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TRPC6 Cation Channel / genetics
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TRPC6 Cation Channel / metabolism
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Zinc Finger E-box Binding Homeobox 2 / genetics
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Zinc Finger E-box Binding Homeobox 2 / metabolism
Substances
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ARNT protein, human
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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TRPC6 Cation Channel
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TRPC6 protein, human
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ZEB2 protein, human
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Zinc Finger E-box Binding Homeobox 2
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Aryl Hydrocarbon Receptor Nuclear Translocator