title: Rho-kinase inhibition prevents the progression of diabetic nephropathy by downregulating hypoxia-inducible factor 1α.
abstract: The small GTPase Rho and its effector Rho-kinase are involved in the pathogenesis of diabetic nephropathy. Accumulating evidence shows that hypoxia-inducible factor-1α (HIF-1α) is a key regulator of renal sclerosis under diabetic conditions. However, the interactions of Rho-kinase and HIF-1α in the development of renal dysfunction have not been defined. Here, we assessed whether Rho-kinase blockade attenuates HIF-1α induction and the subsequent fibrotic response using type 2 diabetic mice and cultured mesangial cells. Fasudil, a Rho-kinase inhibitor, reduced urinary albumin excretion, mesangial matrix expansion, and the expression of fibrotic mediators in db/db mice. Mechanistically, HIF-1α accumulation and the expression of its target genes that contribute to diabetic glomerulosclerosis were also prevented by fasudil in the renal cortex. In mesangial cells, Rho/Rho-kinase signaling was activated under hypoxic conditions. Further in vitro studies showed that pharmacological and genetic inhibition of Rho-kinase promoted proteasomal HIF-1α degradation, which subsequently suppressed HIF-1-dependent profibrotic gene expression by upregulation of prolyl hydroxylase 2. Thus, we found a previously unrecognized renoprotective mechanism for the effects of Rho-kinase inhibition and this could be a potential therapeutic target for the treatment of diabetic nephropathy.
authors.affiliation: Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Matoba
authors.forename: Daiji
authors.initials: D
authors.lastname: Kawanami
authors.forename: Rina
authors.initials: R
authors.lastname: Okada
authors.forename: Masami
authors.initials: M
authors.lastname: Tsukamoto
authors.forename: Jun
authors.initials: J
authors.lastname: Kinoshita
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ito
authors.forename: Sho
authors.initials: S
authors.lastname: Ishizawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kanazawa
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Yokota
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Murai
authors.forename: Senya
authors.initials: S
authors.lastname: Matsufuji
authors.forename: Junko
authors.initials: J
authors.lastname: Takahashi-Fujigasaki
authors.forename: Kazunori
authors.initials: K
authors.lastname: Utsunomiya
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000419:Albuminuria / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects*; D005355:Fibrosis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism; D007672:Kidney Cortex / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D054460:rho-Associated Kinases; C049347:fasudil