Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0920646 (renal ischemia)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxygen tensions in the kidney are heterogeneous, and their changes presumably play an important role in renal physiologic and pathophysiologic processes. A family of hypoxia-inducible transcription factors (HIF) have been identified as mediators of transcriptional responses to hypoxia, which include the regulation of erythropoietin, metabolic adaptation, vascular tone, and neoangiogenesis. In vitro, the oxygen-regulated subunits HIF-1alpha and -2alpha are expressed in inverse relationship to oxygen tensions in every cell line investigated to date. The characteristics and functional significance of the HIF response in vivo are largely unknown. High-amplification immunohistochemical analyses were used to study the expression of HIF-1alpha and -2alpha in kidneys of rats exposed to systemic hypoxia bleeding anemia, functional anemia (0.1% carbon monoxide), renal ischemia, or cobaltous chloride (which is known to mimic hypoxia). These treatments led to marked nuclear accumulation of HIF-1alpha and -2alpha in different renal cell populations. HIF-1alpha was mainly induced in tubular cells, including proximal segments with exposure to anemia/carbon monoxide, in distal segments with cobaltous chloride treatment, and in connecting tubules and collecting ducts with all stimuli. Staining for HIF-1alpha colocalized with inducible expression of the target genes heme oxygenase-1 and glucose transporter-1. HIF-2alpha was not expressed in tubular cells but was expressed in endothelial cells of a small subset of glomeruli and in peritubular endothelial cells and fibroblasts. The kidney demonstrates a marked potential for upregulation of HIF, but accumulation of HIF-1alpha and HIF-2alpha is selective with respect to cell type, kidney zone, and experimental conditions, with the expression patterns partly matching known oxygen profiles. The expression of HIF-2alpha in peritubular fibroblasts suggests a role in erythropoietin regulation.
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PMID:Expression of hypoxia-inducible factor-1alpha and -2alpha in hypoxic and ischemic rat kidneys. 1208 96

The Rab GTPase-activating protein TBC1D4 (AS160) controls trafficking of the glucose transporter GLUT4 in adipocytes and skeletal muscle cells. TBC1D4 is also highly abundant in the renal distal tubule, although its role in this tubule is so far unknown. In vitro studies suggest that it is involved in the regulation of renal transporters and channels such as the epithelial sodium channel (ENaC), aquaporin-2 (AQP2), and the Na+-K+-ATPase. To assess the physiological role of TBC1D4 in the kidney, wild-type (TBC1D4+/+) and TBC1D4-deficient (TBC1D4-/-) mice were studied. Unexpectedly, neither under standard nor under challenging conditions (low Na+/high K+, water restriction) did TBC1D4-/- mice show any difference in urinary Na+ and K+ excretion, urine osmolarity, plasma ion and aldosterone levels, and blood pressure compared with TBC1D4+/+ mice. Also, immunoblotting did not reveal any change in the abundance of major renal sodium- and water-transporting proteins [Na-K-2Cl cotransporter (NKCC2) NKCC2, NaCl cotransporter (NCC), ENaC, AQP2, and the Na+-K+-ATPase]. However, the abundance of GLUT4, which colocalizes with TBC1D4 along the distal nephron of TBC1D4+/+ mice, was lower in whole kidney lysates of TBC1D4-/- mice than in TBC1D4+/+ mice. Likewise, primary thick ascending limb (TAL) cells isolated from TBC1D4-/- mice showed an increased basal glucose uptake and an abrogated insulin response compared with TAL cells from TBC1D4+/+ mice. Thus, TBC1D4 is dispensable for the regulation of renal Na+ and water transport, but may play a role for GLUT4-mediated basolateral glucose uptake in distal tubules. The latter may contribute to the known anaerobic glycolytic capacity of distal tubules during renal ischemia.
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PMID:Rab-GAP TBC1D4 (AS160) is dispensable for the renal control of sodium and water homeostasis but regulates GLUT4 in mouse kidney. 2633 59

Multiple large clinical trials have shown that sodium-glucose cotransporter (SGLT) 2 inhibitors reduce the risk of renal events. However, the mechanism responsible for this outcome remains unknown. Here we investigated the effects of the SGLT2 inhibitor luseogliflozin on the development of renal fibrosis after renal ischemia/reperfusion injury in non-diabetic mice. Luseogliflozin significantly suppressed development of renal fibrosis, prevented peritubular capillary congestion/hemorrhage, attenuated CD31-positive cell loss, suppressed hypoxia, and increased vascular endothelial growth factor (VEGF)-A expression in the kidney after ischemia/reperfusion injury. Luseogliflozin failed to induce the above-mentioned protection in animals co-treated with sunitinib, a VEGF receptor inhibitor. Additionally, luseogliflozin reduced glucose uptake and increased VEGF-A expression in the kidneys of glucose transporter 2 (GLUT2)-downregulated mice following ischemia/reperfusion and in GLUT2-knock-down cells compared with those in normal controls. Withdrawal of glucose from cultured medium, to halt glucose uptake, remarkably increased VEGF-A expression and reversed the luseogliflozin-induced increase in VEGF-A expression in the proximal tubular cells. Thus, luseogliflozin prevented endothelial rarefaction and subsequent renal fibrosis after renal ischemia/reperfusion injury through a VEGF-dependent pathway induced by the dysfunction of proximal tubular glucose uptake in tubules with injury-induced GLUT2 downregulation.
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PMID:A sodium-glucose cotransporter 2 inhibitor attenuates renal capillary injury and fibrosis by a vascular endothelial growth factor-dependent pathway after renal injury in mice. 3014 67