Rho kinase inhibition by fasudil attenuates cyclosporine-induced kidney injury

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 338; no. 1; pp. 271 - 279
• Main Authors: Park, Jeong Woo, Park, Cheon Hoon, Kim, In Jin, Bae, Eun Hui, Ma, Seong Kwon, Lee, Jong Un, Kim, Soo Wan
• Format: Journal Article
• Language: English
• Published: United States 01.07.2011
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - therapeutic use; Animals; Cells, Cultured; Cyclosporine - toxicity; Kidney Cortex - drug effects; Kidney Cortex - enzymology; Kidney Cortex - pathology; Kidney Diseases - chemically induced; Kidney Diseases - enzymology; Kidney Diseases - prevention & control; Male; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Rats; Rats, Sprague-Dawley; rho-Associated Kinases - antagonists & inhibitors; rho-Associated Kinases - biosynthesis; rho-Associated Kinases - physiology; Signal Transduction - drug effects; Signal Transduction - physiology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.111.179457

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.