title: Impact of the hypoxia-inducible factor-1 α (HIF1A) Pro582Ser polymorphism on diabetes nephropathy.
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 α subunit (HIF1A) genetic polymorphisms on the development of DN.
  
  
  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.
authors.affiliation: Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. harvest.gu@ki.se
authors.forename: Harvest F
authors.initials: HF
authors.lastname: Gu
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zheng
authors.forename: Norhashimah
authors.initials: N
authors.lastname: Abu Seman
authors.forename: Tianwei
authors.initials: T
authors.lastname: Gu
authors.forename: Ileana Ruxandra
authors.initials: IR
authors.lastname: Botusan
authors.forename: Vivekananda Gupta
authors.initials: VG
authors.lastname: Sunkari
authors.forename: Ezarul Faradianna
authors.initials: EF
authors.lastname: Lokman
authors.forename: Kerstin
authors.initials: K
authors.lastname: Brismar
authors.forename: Sergiu-Bogdan
authors.initials: SB
authors.lastname: Catrina
mesh_terms: D000328:Adult; D002460:Cell Line; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics* / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D051793:Hypoxia-Inducible Factor 1