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.

Recovery from Glycerol-Induced Acute Kidney Injury Is Accelerated by Suramin

“…Suramin exerts this beneficial effect through the inhibition of apoptosis, decreased activation of endothelial cells, decreased inflammatory signaling molecules and infiltration of inflammatory cells, decreased oxidative stress, and increased tubular cell proliferation. These results are consistent with previous studies of glycerol-induced AKI in which oxidative stress, apoptosis, and inflammation are key mediators of renal dysfunction (Homsi et al, 2006;Rosenberger et al, 2008;Homsi et al, 2010;Kim et al, 2010;Wang et al, 2011;Wei et al, 2011). A proinflammatory response and leukocyte infiltration are important mechanisms in the initiation and maintenance of glycerol-induced AKI (Bonventre and Zuk, 2004;Homsi et al, 2006;de Jesus Soares et al, 2007).…”

“…Caspase-3-mediated apoptosis has been implicated in tubular damage after glycerol-induced AKI (Padanilam, 2003;Homsi et al, 2010;Wang et al, 2011). Suramin decreased renal cleaved caspase-3 at 48 h after glycerol treatment compared with glycerol treatment alone at the same time point (Fig.…”

“…Recent studies have demonstrated that timely prophylactic and/or early therapeutic interventions (either pre-or coadministration) ameliorated glycerol-induced AKI (Homsi et al, 2010;Kim et al, 2010;Wang et al, 2011;Wei et al, 2011). However, no reports have documented the efficacy of the delayed intervention of a therapeutic agent when the renal dysfunction is already well established.…”

“…Although the pathogenesis of glycerol-induced AKI is complex and incompletely understood (Vanholder et al, 2000), apoptosis (Homsi et al, 2010;Kim et al, 2010;Wang et al, 2011), inflammation (Homsi et al, 2006), and oxidative stress (Rosenberger et al, 2008;Kim et al, 2010;Wei et al, 2011) have been implicated. Recent studies have demonstrated that timely prophylactic and/or early therapeutic interventions (either pre-or coadministration) ameliorated glycerol-induced AKI (Homsi et al, 2010;Kim et al, 2010;Wang et al, 2011;Wei et al, 2011).…”

Antioxidant and Nephroprotective Activities of Aconitum heterophyllum Root in Glycerol Induced Acute Renal Failure in Rats

“…Glycerol induces damage by oxidative stress, apoptosis, and inflammation is key mediator of renal dysfunction [40][41][42][43][44][45]. The association between oxidative stress and nephrotoxicity has been well established in many experimental animal models.…”