Impact of the Hypoxia-Inducible Factor-1 α (HIF1A) Pro582Ser Polymorphism on Diabetes Nephropathy
- Harvest F. Gu, PHD1⇓,
- Xiaowei Zheng, MD, PHD1,
- Norhashimah Abu Seman, BSC1,2,
- Tianwei Gu, MD1,
- Ileana Ruxandra Botusan, MD1,
- Vivekananda Gupta Sunkari, MSC1,
- Ezarul Faradianna Lokman, MSC1,2,
- Kerstin Brismar, MD, PHD1 and
- Sergiu-Bogdan Catrina, MD, PHD1⇓
- 1Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
- 2Cardiovascular, Diabetes and Nutrition Research Centre, Institute for Medical Research, Kuala Lumpur, Malaysia
- Corresponding authors: Harvest F. Gu, , and Sergiu-Bogdan Catrina, .
OBJECTIVE Hypoxia plays a major pathogenic role in diabetic nephropathy (DN). We have investigated in this study the effect of hypoxia-inducible factor 1 α 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-1α in the kidneys of diabetic mice was appreciated by immunohistochemistry, and the effect HIF1A Pro582Ser polymorphism on HIF-1α 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-1α 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-1α.
A slide set summarizing this article is available online.
- Received June 13, 2012.
- Accepted July 19, 2012.
- © 2013 by the American Diabetes Association.
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