Dasatinib mitigates renal fibrosis in a rat model of UUO via inhibition of Src/STAT-3/NF-κB signaling.

Abstract

This research aimed to investigate the reno-protective impact of the tyrosine kinase inhibitor dasatinib (DAS) against renal fibrosis induced by unilateral ureteral obstruction (UUO) in rats. DAS administration improved renal function and mitigated renal oxidative stress with paralleled reduction in the ligated kidney mass index, significant retraction in renal histopathological alterations and suppression of renal interstitial fibrosis. Nevertheless, DAS administration attenuated renal expression of phosphorylated Src (p-Src), Abelson (c-Abl) tyrosine kinases, nuclear factor-kappaB (NF-κB) p65, and phosphorylated signal transducer and activator of transcription-3 (p-STAT-3)/STAT-3 with paralleled reduction in renal contents of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1). DAS diminished interstitial macrophage infiltration and decreased renal profibrotic transforming growth factor-β1 (TGF-β1) levels and suppressed interstitial expression of renal α-smooth muscle actin (α-SMA) and fibronectin. Collectively, DAS slowed the progression of renal interstitial fibrosis, possibly via attenuating renal oxidative stress, impairing Src/STAT-3/NF-κB signaling, and reducing renal inflammation.