title: Rho kinase inhibition by fasudil attenuates cyclosporine-induced kidney injury.
abstract: It has been shown that the inhibition of the Rho/Rho kinase (ROCK) pathway prevents tubulointerstitial fibrosis and ameliorates renal function in various progressive renal disorders. The present study was to determine whether fasudil, a ROCK inhibitor, has a protective effect on cyclosporine A (CsA)-induced nephropathy. Male Sprague-Dawley rats were treated with CsA (n = 10, 20 mg · kg(-1) day(-1) s.c.), CsA + fasudil (n = 10, 3 mg · kg(-1) day(-1) i.p.), or vehicle alone (n = 10) for 28 days. Fasudil cotreatment ameliorated CsA-induced changes and restored renal function. CsA decreased the expression of endothelial nitric-oxide synthase and increased inducible nitric-oxide synthase/3-nitrotyrosine in the kidney. Accordingly, there was infiltration of inflammatory cells and up-regulation of inflammatory cytokines. Fasudil also significantly suppressed the expression of transforming growth factor-β1, Smad signaling, and subsequent epithelial-to-mesenchymal processes. In addition, fasudil augmented p27(kip1) expression and decreased the number of proliferating cell nuclear antigen-positive cells. In another series of experiments using HK-2 cells in culture, fasudil also suppressed CsA-induced increases in mitogen-activated protein kinase phosphorylation. CsA induced expression of p53, the degree of which was attenuated by fasudil in association with decreases of proapoptotic markers such as Bad, Bax, and total/cleaved caspase-3. These results suggest that inhibition of the Rho/ROCK pathway attenuates CsA-induced nephropathy through the suppression of the induction of inflammatory, apoptotic, and fibrogenic factors, along with inhibition of Smad, mitogen-activated protein kinases, and nitric oxide signaling pathways.
authors.affiliation: Department of Internal Medicine, Chonnam National University Medical School, Gwangju, South Korea.
authors.forename: Jeong Woo
authors.initials: JW
authors.lastname: Park
authors.forename: Cheon Hoon
authors.initials: CH
authors.lastname: Park
authors.forename: In Jin
authors.initials: IJ
authors.lastname: Kim
authors.forename: Eun Hui
authors.initials: EH
authors.lastname: Bae
authors.forename: Seong Kwon
authors.initials: SK
authors.lastname: Ma
authors.forename: Jong Un
authors.initials: JU
authors.lastname: Lee
authors.forename: Soo Wan
authors.initials: SW
authors.lastname: Kim
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002478:Cells, Cultured; D016572:Cyclosporine / Q000633:toxicity*; D007672:Kidney Cortex / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000517:prevention & control*; D008297:Male; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology
chemical_list: D047428:Protein Kinase Inhibitors; D016572:Cyclosporine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil