Abstract
Diabetic nephropathy (DN) is now a leading cause of end-stage renal disease. In addition, DN accounts for the increased mortality in type 1 and type 2 diabetes, and then patients without DN achieve long-term survival compatible with general population. Hypoxia represents an early event in the development and progression of DN, and hypoxia-inducible factor- (HIF-) 1 mediates the metabolic responses to renal hypoxia. Diabetes induces the “fraternal twins” of hypoxia, that is, pseudohypoxia and hypoxia. The kidneys are susceptible to hyperoxia because they accept 20% of the cardiac output. Therefore, the kidneys have specific vasculature to avoid hyperoxia, that is, AV oxygen shunting. The NAD-dependent histone deacetylases (HDACs) sirtuins are seven mammalian proteins, SIRTs 1–7, which are known to modulate longevity and metabolism. Recent studies demonstrated that some isoforms of sirtuins inhibit the activation of HIF by deacetylation or noncatalyzing effects. The kidneys, which have a vascular system that protects them against hyperoxia, unfortunately experience extraordinary hypernutrition today. Then, an unexpected overload of glucose augments the oxygen consumption, which ironically results in hypoxia. This review highlights the primary role of HIF in diabetic kidneys for the metabolic adaptation to diabetes-induced hypoxia.
Highlights
Tissue oxygen tension is determined by the balance between the blood flow and tissue oxygen consumption
Increased renal blood flow increases the glomerular filtration rate, which in turn increases the rate of sodium reabsorption, which increases the tissue oxygen consumption
In diabetic kidney, hyperfiltration triggers a vicious circle between increasing oxygen delivery and increasing oxygen consumption that leads to more needs for oxygen supply
Summary
Diabetic nephropathy (DN) is a leading cause of endstage renal disease (ESRD) and constitutes a major factor in progressive kidney disease. In an in vitro study, high glucose failed to induce or enhance the expression of HIF-1α protein in human renal proximal tubular cells (HRPTECs) in normoxia or in hypoxia, respectively [21] It was found in the same study that high glucose abolished the Pasteur effects, which are adaptive responses to hypoxic stress by decreased oxidative phosphorylation and an increase in anaerobic fermentation, and that high glucose decreased mitochondrial efficiency by uncoupling oxygen consumption from ATP production [21]. In another cultured system, high glucose blunted the vascular endothelial growth factor (VEGF) response to hypoxia in immortalized rat proximal tubular cells via the oxidative stress-regulated HIF/hypoxiaresponsible element (HRE) pathway [22]. In diabetic kidney, hyperglycemia and hypoxia may induce glycolysis partly via activation of NOX4 by providing NAD+ for fuel and by suppressing mitochondrial oxidative phosphorylation
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