title: Involvements of Rho-kinase and TGF-beta pathways in aldosterone-induced renal injury.
abstract: Recent studies have suggested a role for aldosterone in the pathogenesis of renal injury. This study investigated the potential contributions of Rho-kinase and TGF-beta pathways to aldosterone-induced renal injury. Rats were uninephrectomized and then treated for 5 wk with 1% NaCl in a drinking solution and one of the following: Vehicle (2% ethanol, subcutaneously; n = 9); aldosterone (0.75 microg/h, subcutaneously; n = 9); or aldosterone + fasudil, a specific Rho-kinase inhibitor (10 mg/kg per d, subcutaneously; n = 8). Phosphorylation of myosin phosphate target subunit-1 (MYPT1) and Smad2/3 in renal cortical tissue was measured by Western blotting with anti-phospho MYPT1 and Smad2/3 antibodies, respectively. Rats that received aldosterone infusion exhibited hypertension and severe renal injury characterized by proteinuria, glomerular sclerosis, and tubulointerstitial fibrosis with increases in alpha-smooth muscle actin staining and numbers of monocytes/macrophages in the interstitium. Renal cortical mRNA levels of types I and III collagen, TGF-beta, connective tissue growth factor, and monocyte chemoattractant protein-1 as well as Smad2/3 phosphorylation were significantly increased in rats that received aldosterone infusion. All of these changes were associated with an increase in renal tissue MYPT1 phosphorylation. Treatment with fasudil did not alter BP but significantly ameliorated proteinuria and renal injury in rats that received aldosterone infusion. Furthermore, fasudil prevented MYPT1 phosphorylation and markedly decreased alpha-smooth muscle actin staining, numbers of monocytes/macrophages, mRNA levels of types I and III collagen, TGF-beta, connective tissue growth factor and monocyte chemoattractant protein-1, and Smad2/3 activity in renal cortical tissues. These results provide evidence, for the first time, that Rho-kinase is substantially involved in aldosterone-induced renal injury through activation of a TGF-beta-dependent pathway.
authors.affiliation: Department of CardioRenal and Cerebrovascular Medicine, Kagawa University Medical School, Kagawa, Japan.
authors.forename: Guang-Ping
authors.initials: GP
authors.lastname: Sun
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohno
authors.forename: Peng
authors.initials: P
authors.lastname: Guo
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Nagai
authors.forename: Kayoko
authors.initials: K
authors.lastname: Miyata
authors.forename: Yu-Yan
authors.initials: YY
authors.lastname: Fan
authors.forename: Shoji
authors.initials: S
authors.lastname: Kimura
authors.forename: Hideyasu
authors.initials: H
authors.lastname: Kiyomoto
authors.forename: Koji
authors.initials: K
authors.lastname: Ohmori
authors.forename: De-Tian
authors.initials: DT
authors.lastname: Li
authors.forename: Youichi
authors.initials: Y
authors.lastname: Abe
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000450:Aldosterone / Q000502:physiology*; D000818:Animals; D004789:Enzyme Activation; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D008297:Male; D009392:Nephrectomy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D054460:rho-Associated Kinases
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D016212:Transforming Growth Factor beta; D000450:Aldosterone; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C049347:fasudil