Fasudil Ameliorates Rhabdomyolysis-Induced Acute Kidney Injury via Inhibition of Apoptosis

Abstract

During times of war or natural disasters, rhabdomyolysis leading to acute kidney injury (AKI) can assume epidemic proportions. Fasudil attenuates ischemia/reperfusion-induced AKI. We investigated the therapeutic effect of an early application of fasudil on AKI induced by rhabdomyolysis and explored the potential mechanisms. Male Wistar rats were randomly divided into a control group (saline, 7 mL/kg, i.m.), a Gly group (50% glycerol, 7 mL/kg, i.m.), and a fasudil group (50% glycerol, 7 mL/kg, i.m.; fasudil, 20 mg/kg bodyweight, i.p., three times every 24 h beginning 72 h before glycerol administration). Serum creatinine, blood urea nitrogen (BUN), and histopathological changes were used to demonstrate kidney function 24 h after the glycerol injection. Cell apoptosis and the expression of rho-associated protein kinase member (ROCK1), phosphatase and tensin homolog (PTEN), P-Akt, and caspase-8, -9, and -3 were measured. Serum creatinine and BUN levels increased significantly in Gly group compared with control group. Both levels decreased after fasudil treatment. The renal tubular damage score was significantly lower and cell apoptosis was significantly less in fasudil group compared with Gly group. The expression levels of ROCK1, PTEN, and caspase-8, -9, and -3 were upregulated significantly in Gly group, and their expression was reduced in the fasudil group. The P-Akt level was decreased in Gly group and upregulated significantly in fasudil group. Early application of fasudil reduced rhabdomyolysis-associated renal injury by inhibiting Rho kinase and thereby activating the PI-3K/Akt pathway, which decreased cell apoptosis via both the intrinsic and extrinsic apoptotic pathways.

• fasudil
• rhabdomyolysis
• acute kidney injury
• apoptosis
• ROCK

ACKNOWLEDGMENTS

This work was supported by the Fund of Chinese PLA Eleventh Five-Year Plan for Medical Sciences (nos. 08Z034, 06Q065) and a grant from the National Basic Research Program of China (nos. 2007CB507400, 2011CB944000).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.