HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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.
AuthorsJeong Woo Park, Cheon Hoon Park, In Jin Kim, Eun Hui Bae, Seong Kwon Ma, Jong Un Lee, Soo Wan Kim
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 338 Issue 1 Pg. 271-9 (Jul 2011) ISSN: 1521-0103 [Electronic] United States
PMID21474569 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Protein Kinase Inhibitors
  • Cyclosporine
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • rho-Associated Kinases
  • fasudil
Topics
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (analogs & derivatives, pharmacology, therapeutic use)
  • Animals
  • Cells, Cultured
  • Cyclosporine (toxicity)
  • Kidney Cortex (drug effects, enzymology, pathology)
  • Kidney Diseases (chemically induced, enzymology, prevention & control)
  • Male
  • Protein Kinase Inhibitors (pharmacology, therapeutic use)
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction (drug effects, physiology)
  • rho-Associated Kinases (antagonists & inhibitors, biosynthesis, physiology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: