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

• Published in: Diabetes care Vol. 36; no. 2; pp. 415 - 421
• Main Authors: Gu, Harvest F., Zheng, Xiaowei, Abu Seman, Norhashimah, Gu, Tianwei, Botusan, Ileana Ruxandra, Sunkari, Vivekananda Gupta, Lokman, Ezarul Faradianna, Brismar, Kerstin, Catrina, Sergiu-Bogdan
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.02.2013
• Subjects: Adult; Biological and medical sciences; Cell Line; Diabetes. Impaired glucose tolerance; Diabetic nephropathies; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; DNA binding proteins; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Genetic aspects; Genetic polymorphisms; Genotype; Humans; Hypoxia-Inducible Factor 1 - genetics; Hypoxia-Inducible Factor 1 - metabolism; Immunohistochemistry; Male; Medical sciences; Metabolic diseases; Middle Aged; Miscellaneous; Original Research; Physiological aspects; Polymorphism, Single Nucleotide - genetics; Public health. Hygiene; Public health. Hygiene-occupational medicine; Malaysia; Endocrinopathy; Kidney disease; Human; Urinary system disease; Nutrition; Diabetes mellitus; Metabolic diseases; Scientific literature; Nephropathy; Impact factor; Transcription factor HIF1; Endocrinology; Polymorphism
• ISSN: 0149-5992; 1935-5548; 1935-5548
• DOI: 10.2337/dc12-1125

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. 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. 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. 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.