Adaptation to hypoxia in the diabetic rat kidney

Abstract

Hypoxia of the kidney in diabetes could predispose it to develop acute and chronic renal failure. To examine the relationship between renal hypoxia and renal failure, we measured hypoxia (as a pimonidazole adducts), hypoxia-inducible factors (HIFs), and a hypoxia target gene heme oxygenase-1. The studies were performed in rats with streptozotocin (STZ)-induced diabetes, Cohen diabetes sensitive rats, and during short-term artificial hyperglycemia in rats induced by intravenous glucose and octreotide. STZ-treated rats received insulin, the superoxide dismutase mimetic tempol, or contrast medium. Radiocontrast media causes hypoxia and HIF induction. Hypoxia, HIFs, and heme oxygenase were undetectable in controls, but transiently activated in STZ-treated and the Cohen diabetes sensitive rats. Different patterns of HIFs and pimonidazole were observed between the three models. Insulin abolished pimonidazole and HIF induction, whereas tempol lead to increased HIFs and heme oxygenase induction at similar levels of pimonidazole. When compared with control rats, STZ-treated rats exhibited more intense and protracted renal pimonidazole, with augmented hypoxia inducible factor production and reduced GFR following contrast media. Our data suggest that both regional hypoxia and hypoxia adaptation transiently occur in early stages of experimental diabetes, largely dependent on hyperglycemia or after contrast media. Tempol may augment the HIF response in diabetes.

Hypoxia-inducible Factors and the Prevention of Acute Organ Injury

“…We also found that HIF-α isoforms are stabilized in acute hypoxic stress, predominantly in the cortex in rhabdomyolysis-induced kidney injury [26], in the outer stripe of the outer medulla following ischemia and reperfusion [27,28], or in the inner stripe and inner medulla following the induction of distal tubular hypoxic injury by radiocontrast agent, or after the inhibition of prostaglandin or NO synthesis or with their combinations [23]. Outer medullary HIF stabilization is also noted in chronic tubulointerstitial disease [29] and in experi mental diabetes [30], again spatially distributed in areas with proven hypoxia. HIF was also detected in biopsies from transplanted kidneys [31].…”

“…Th is situation may lead to HIF de-stabilization and inadequate HIF response to hypoxia. For example, hypoxia-mediated HIF expression in the diabetic renal medulla is substantially improved by the administration of the membrane-permeable superoxide dismutase mimetic tempol [30]. It is, therefore, tempting to assume that ROS scavengers, as well as PHD inhibitors may improve tissue adaptive responses to hypoxia, coupled with oxidative stress.…”

Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db mice as a model of type 2 diabetes

“…UCP-2 is the major isoform in human [15], rat [16] and mouse kidneys [17]. Increased mitochondrial uncoupling mediated by UCP-2 has been reported in kidneys from type 1 diabetic rats [18], resulting in increased oxygen consumption, which can at least partially explain the kidney tissue hypoxia commonly observed in diabetes [9,19]. UCPs are directly activated by superoxide in the kidney [20].…”

Timing of Arteriovenous Fistula Placement

“…In the present issue of JASN, 14 London and colleagues once again blaze the trail by illuminating the physiologic relationships between osteoblast bone anabolic function, parathyroid hormone (PTH) levels, and clinically relevant PAD. In this cohort of 65 well phenotype patients receiving RRT, approximately one third had elevated ABIx values as consistent with prevalent medial artery calcification, 17% had reduced ABIx values indicating atherosclerotic calcification, and half possessed normal indices.…”

“…In this cohort of 65 well phenotype patients receiving RRT, approximately one third had elevated ABIx values as consistent with prevalent medial artery calcification, 17% had reduced ABIx values indicating atherosclerotic calcification, and half possessed normal indices. 14 The authors then analyzed the relationship between intact PTH levels and direct measure of osteoblast anabolic function by dynamic bone histomorphometry, comparing individuals with and without PAD. They reasoned that the slope of the regression relationship between PTH-the prototypic bone anabolic hormone-to direct histologic measures of osteoblast anabolic function (dLS/BS) would provide an index of PTH sensitivity.…”