High glucose activates HIF-1-mediated signal transduction in glomerular mesangial cells through a carbohydrate response element binding protein.
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.
Isoe
Tsubasa
T
Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical College, Asahikawa, Hokkaido, Japan.
Makino
Yuichi
Y
Mizumoto
Katsutoshi
K
Sakagami
Hidemitsu
H
Fujita
Yukihiro
Y
Honjo
Jun
J
Takiyama
Yumi
Y
Itoh
Hiroshi
H
Haneda
Masakazu
M
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
D051793:Hypoxia-Inducible Factor 1; D005947:Glucose