title: High glucose activates HIF-1-mediated signal transduction in glomerular mesangial cells through a carbohydrate response element binding protein.
abstract: High glucose evokes a variety of signals in mesangial cells that alter cellular functions responsible for the development of diabetic glomerulopathy. The hypoxia-inducible factor-1alpha (HIF-1alpha) regulates cellular homeostasis under hypoxic conditions, but it also has pleiotropic effects in response to cellular stresses at normoxia. Here we determined whether HIF-1alpha has a role in the regulation of mesangial cells in hyperglycemia. In the streptozotocin-induced diabetic mouse model, glomerular mesangial cells had a significant increase in HIF-1alpha expression in the nucleus. In cultured mesangial cells, high glucose enhanced the expression of HIF-1alpha and its target genes known to be involved in the development of diabetic glomerulopathy. A glucose-responsive carbohydrate response element binding protein (ChREBP) was found to have a critical role in the transcriptional upregulation of HIF-1alpha and downstream gene expression in mesangial cells exposed to high glucose. Knockdown of HIF-1alpha or ChREBP in mesangial cells abrogated the high glucose-mediated perturbation of gene expression. Our results show that ChREBP and HIF-1alpha mediate gene regulation in mesangial cells. Further studies will be needed to find out whether these findings are relevant to the development of the diabetic nephropathy.
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical College, Asahikawa, Hokkaido, Japan.
authors.forename: Tsubasa
authors.initials: T
authors.lastname: Isoe
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Makino
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Mizumoto
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Sakagami
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Fujita
authors.forename: Jun
authors.initials: J
authors.lastname: Honjo
authors.forename: Yumi
authors.initials: Y
authors.lastname: Takiyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
authors.forename: Masakazu
authors.initials: M
authors.lastname: Haneda
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020218:Response Elements / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051793:Hypoxia-Inducible Factor 1; D005947:Glucose