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

• Autores: Harvest F. Gu, Xiaowei Zheng, Norhashimah Abu Seman, Tianwei Gu, Ileana Ruxandra Botusan, Vivekananda Gupta Sunkari, Ezarul Faradianna Lokman, Kerstin Brismar, Sergiu-Bogdan Catrina
• Localización: Diabetes care, ISSN-e 0149-5992, Vol. 36, Nº. 2, 2013, págs. 415-421
• Idioma: inglés
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• Resumen

  • Abstract 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 diabetic mice 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.