2013

Harvest G Gu, Xiaowei Zheng, Norhashimah Abu Seman, Tianwe Gu, Ileana Ruxandra Botusan, Vivekananda Gupta Sunkari, Ezarul Faradianna Lokman, Kerstin Brismar and Sergiu-Bogdan Catrina (2013). Impact of the hypoxia-inducible factor-1 alpha (HIF1A) pro582ser polymorphism on diabetes nephropathy. Diabetes Care 36(2): 415-421

OBJECTIVE - Hypoxia plays a major pathogenic role in diabetic nephropathy (DN). We have investigated in this study the effect of hypoxia-inducible factor 1 a 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-1a in the kidneys of diabeticmice was appreciated by immunohistochemistry, and the effect HIF1A Pro582Ser polymorphism on HIF-1a 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-1a 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-1a.