Rho-Associated Kinase Inhibitor Fasudil Protects from Sepsis-Induced Acute Kidney Injury in Rat via Suppressing STAT-3 and NLRP-3 Pathway

Abstract

Sepsis-associated acute kidney injury (S-AKI) is a severe complication in critically ill patients, marked by inflammation, oxidative stress, and renal dysfunction. This study aimed to evaluate the renoprotective effects of Fasudil (Fas), a Rho-associated kinase inhibitor, in a rat model of S-AKI induced by cecal ligation and puncture (CLP). Thirty-six Wistar albino rats were divided into control, CLP with saline, and Fas (100 mg/kg/day intraperitoneally) groups. Biochemical, histopathological, and molecular analyses were conducted to assess kidney function, oxidative stress, and inflammation. Fas treatment significantly decreased plasma malondialdehyde and TNF-α levels, reducing oxidative stress and systemic inflammation. Kidney function markers, including BUN and creatinine, showed marked improvement. Furthermore, Fas suppressed the expression of STAT-3 and NLRP-3 in renal tissues, highlighting its role in modulating key inflammatory pathways. Histological evaluation revealed alleviated renal damage, with less tubular necrosis and interstitial inflammation in the Fas-treated group. In conclusion, Fas demonstrates significant anti-inflammatory, antioxidant, and nephroprotective effects in S-AKI, primarily by inhibiting STAT-3 and NLRP-3 signaling. These results support its potential as a therapeutic agent in sepsis-induced kidney injury and suggest the need for further clinical evaluation.

Keywords: Fasudil; NLRP-3 inflammasome; Rho kinase inhibitor; STAT-3 pathway; sepsis-associated acute kidney injury.

Figure 1

Kaplan–Meier survival curves for the three groups over 5 days. Statistical comparison is done using the Log-Rank (Mantel–Cox) test.

Figure 2

Histopathological evaluations of the kidney are graphically presented. Results were presented as mean ± SEM. Statistical analyses were performed using one-way ANOVA and a post hoc Bonferroni test. * p < 0.001, different from normal groups; # p < 0.05, ## p < 0.001 different from CLP and saline group.

Figure 3

Kidney histopathology ×10, ×20, and ×40 magnification, hematoxylin and eosin (H&E) stain. (A–C) Normal group kidney, renal tubules (t); glomerulus (G); (D–F) CLP and saline groups showed severe histopathologic alteration showed kidney injury for tubular dilatation (td), tubular epithelial necrosis (arrow), hemorrhage (H), and luminal necrotic debris (asterisks); (G–I) CLP and 100 mg/kg Fasudil groups showed decreased injury for normal tubules (t) and tubular epithelial cells (arrow).