Impact of the Hypoxia-Inducible Factor-1 α (HIF1A) Pro582Ser Polymorphism on Diabetes Nephropathy

OBJECTIVE-Hypoxia plays a major pathogenic role in diabetic nephropathy (DN). We have investigated in this study the effect of hypoxia-inducible factor 1 alpha subunit (HIF1A) genetic polymorphisms on the development of DN. RESEARCH DESIGN AND METHODS-In 1,165 American type 1 diabetic patients with and without DN selected from the Genetics of Kidneys in Diabetes (GoKinD) study, the HIF1A genetic polymorphisms were genotyped with TaqMan allelic discrimination. The regulation of HIF-1 alpha in the kidneys of diabetic mice was appreciated by immunohistochemistry, and the effect HIF1A Pro582Ser polymorphism on HIF-1 alpha sensitivity to glucose was evaluated in vitro. RESULTS-We identified a protective association between HIF1A Pro582Ser polymorphism and DN in male subjects. We also provided mechanistic insights that HIF-1 alpha is repressed in the medulla of diabetic mice despite hypoxia and that Pro582Ser polymorphism confers less sensitivity to the inhibitory effect of glucose during a hypoxic challenge. CONCLUSIONS-The current study demonstrates for the first time that HIF1A Pro582Ser polymorphism has an effect on DN, possibly by conferring a relative resistance to the repressive effect of glucose on HIF-1 alpha. Diabetes Care 36:415-421, 2013