The therapeutic use of numerous pharmacological agents may be limited due to their nephrotoxicity and associated kidney injury. The aim of our study is to test the hypothesis that the blockade of tyrosine kinase-linked receptors signaling protects against chemically induced nephrotoxicity. To test our hypothesis, we investigated sunitinib as an inhibitor for tyrosine kinase signaling for both vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptors (PDGFR) against adenine-induced nephrotoxicity. Four groups of adult male Swiss albino mice were investigated: normal group, adenine group, sunitinib group, and the adenine+sunitinib group that received concurrent administration for both adenine and sunitinib. Kidney function and oxidative stress biomarkers were analyzed. Tubular injury and histopathological changes were examined. Renal expression of B-cell lymphoma-2 (Bcl-2), the tumor suppressor p53, transforming growth factor beta-1 (TGF-β1), phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2), and phospho-signal transducer and activator of transcription (phospho-STAT3) were measured. The results obtained showed significant improvement (p < 0.05) in kidney function and antioxidant biomarkers in the adenine+sunitinib group. Kidney fibrosis and tubular injury scores were significantly (p < 0.05) less in the adenine+sunitinib group and that of p53 expression as well. Furthermore, sunitinib decreased (p < 0.5) renal levels of TGF-β1, p-ERK1/2, and phospho-STAT3 while elevating Bcl-2 expression score. In conclusion, sunitinib diminished adenine-induced nephrotoxicity through interfering with profibrogenic pathways, activating anti-apoptotic mechanisms, and possessing potential antioxidant capabilities.

Background/Objectives: Autoimmune hepatitis (AIH) is a liver injury characterized by the dysregulation of immune responses. Current options for AIH have limitations that highlight the urgent need to investigate alternative or adjunct therapeutic strategies for its management. We aimed to explore the protective effects of fasudil against concanavalin A (Con A)-induced AIH in mice. Con A resulted in significant hepatic damage, evidenced by dysregulation in liver function biomarkers, marked inflammatory cell infiltration, and hepatocellular degeneration. Methods: The pretreatment of mice with fasudil (10 and 25 mg/kg, intraperitoneally) for 7 days resulted in a significant ameliorative effect on these alterations in a dose-dependent manner. Fasudil treatment was associated with suppression of the RhoA/Rho-associated coiled-coil-containing protein kinase (ROCK) pathway and concomitant downregulation of toll-like receptor 4 (TLR4)/Nuclear factor-κB (NF-κB). Results: These changes were accompanied by reduced macrophage activation and the reduction of pro-inflammatory cytokines, as evidenced by decreased nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interferon gamma (INF-γ), and interleukin-17A (IL-17A). Moreover, it significantly limited the cluster of differentiation (CD)4⁺ and CD8⁺ T cell infiltration, thereby modulating adaptive immune amplification. Conclusions: Accordingly, fasudil restored redox homeostasis and mitigated hepatocellular death by rebalancing apoptotic regulators, normalizing the expression of B cell lymphoma 2 (BCL-2) while reducing the expression of BCL-2-associated X protein (BAX) and caspase-3 activation. Subsequently, fasudil improved liver function profiles and preserved hepatic architecture. Our results demonstrate that fasudil has potent immunomodulatory, anti-inflammatory, antioxidant, and anti-apoptotic effects in AIH. Its protective effects are associated with the suppression of RhoA/ROCK and TLR4/NF-κB signaling, supporting further investigation into the contribution of these pathways to the therapeutic actions of fasudil in AIH.