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

• Published in: Environmental toxicology and pharmacology Vol. 84; p. 103625
• Main Authors: Hassan, Nabila M.E., Shehatou, George S.G., Kenawy, Hany Ibrahim, Said, Eman
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2021; Elsevier Science Ltd
• Subjects: Actin; Animals; CD68; Cytokines - immunology; Dasatinib; Dasatinib - pharmacology; Dasatinib - therapeutic use; Disease Models, Animal; Enzyme inhibitors; Fibronectin; Fibrosis; Growth factors; IL-1β; Interleukins; Kidney - drug effects; Kidney - immunology; Kidney - metabolism; Kidney - pathology; Kinases; Macrophages; Macrophages - drug effects; Macrophages - immunology; Male; Metastases; Monocyte chemoattractant protein; Monocyte chemoattractant protein 1; Monocytes; Muscles; NF-kappa B - metabolism; NF-κB protein; Oxidative stress; Oxidative Stress - drug effects; p-Src; Protective Agents - pharmacology; Protective Agents - therapeutic use; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase; Proto-Oncogene Proteins c-abl - metabolism; Rats; Rats, Sprague-Dawley; Reduction; Renal function; Signal Transduction - drug effects; Signaling; Smooth muscle; Src protein; src-Family Kinases - metabolism; STAT-3; Stat3 protein; STAT3 Transcription Factor - metabolism; Transcription; Transforming growth factor-b1; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Tyrosine; Unilateral ureteral obstruction (UUO); Ureteral Obstruction - drug therapy; Ureteral Obstruction - immunology; Ureteral Obstruction - metabolism; Ureteral Obstruction - pathology; α-SMA; Dasatinib; α-SMA; STAT-3; CD68; Unilateral ureteral obstruction (UUO); p-Src
• ISSN: 1382-6689; 1872-7077
• DOI: 10.1016/j.etap.2021.103625

•Dasatinib mitigates renal fibrosis in a rat model of UUO.•Dasatinib mitigates renal oxidative stress.•Dasatinib attenuates renal protein expression of p-Src, c-Abl, NF-κB p65, and p-STAT-3/STAT-3.•Dasatinib reduces renal levels of the proinflammatory cytokines TNF-α, IL-1β and MCP.•Dasatinib decreases renal profibrotic TGF-β1 level and the myofibroblast marker α-SMA. 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.