It has been shown that an inhibition of Rho/Rho-kinase (ROCK) pathway prevents tubulointerstitial fibrosis and ameliorates renal function in various progressive renal disorders. The present study was aimed to determine whether fasudil, a ROCK inhibitor, has a protective effect on cyclosporine (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, along with a restoration of the renal function. CsA decreased the expression of endothelial nitric oxide synthase (NOS) and increased inducible NOS/3-nitrotyrosine in the kidney. Accordingly, there were infiltration of inflammatory cells and upregulation 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 p27kip1 expression and decreased the number of PCNA-positive cells. It also significantly suppressed the expression of transforming growth factor-β1, Smad signaling, and subsequent epithelial-to-mesenchymal processes. In another series of experiment using HK-2 cells in culture, fasudil also suppressed the CsA-induced increases in mitogen-activated protein kinase (MAPK) phosphorylation. CsA induced an expression of p53, the degree of which was attenuated by fasudil in association with decreases of pro-apoptotic markers such as Bad, Bax, and total/cleaved caspase-3. These results suggest that an inhibition of Rho/ROCK pathway attenuate CsA-induced nephropathy through suppressing the induction of inflammatory, apoptotic, and fibrogenic factors, along with inhibition of Smad, MAPKs, and nitric oxide signaling pathways.
- Received January 20, 2011.
- Revision received April 5, 2011.
- Accepted April 6, 2011.
- The American Society for Pharmacology and Experimental Therapeutics