Induction of HIF normalizes oxygen utilization and oxygenation in the diabetic kidney

Abstract

Hyperglycemia results in increased oxygen consumption (QO2) and decreased oxygen tension (pO2) in the kidney. We hypothesize that activation of hypoxia‐inducible factors (HIF) protect against diabetes‐induced alterations in kidney function and oxygen metabolism.The experimental groups consisted of control and streptozotocin‐induced diabetic rats with and without chronic cobalt chloride (CoCl2; inducer of HIF; n=9–10/group).Diabetic rats had increased glomerular filtration rate (2.3±0.2 vs 1.5±0.2 ml/min/kidney; P<0.05) and CoCl2 prevented this increase (1.5±0.1 ml/min/kidney). QO2 was increased in the diabetic kidney (23±2 vs 11±2 μmol/min/kidney; P<0.05) and CoCl2 prevented this alteration (12±2 μmol/min/kidney). Tubular sodium transport (TNa)/QO2 was decreased in the diabetics (14±2 vs 33±8; P<0.05), which was prevented by CoCl2 (25±4). Diabetic kidneys had reduced pO2 in both cortex and medulla compared to control (29±1 vs 45±2 and 22±1 vs 30±1 mmHg, respectively; both P<0.05). CoCl2 prevented these decreases (cortex 42±1; medulla 39±1 mmHg). All investigated parameters were unaltered by CoCl2 in control rats.Diabetes‐induced alteration in kidney oxygen metabolism is prevented by HIF activation via two different mechanisms. Normalizing GFR, which reduces tubular electrolyte load, and maintaining TNa/QO2 contribute to normal QO2 and pO2 in the diabetic kidney. Early pharmacological activation of the HIF system may prevent the development of diabetic nephropathy. Funding: NIH/NIDDK DK077858 and Swedish Research Council.