Fisetin alleviates unilateral ureteral obstruction-induced renal interstitial fibrosis by inhibiting Src activation to block macrophage-myofibroblast transition

Abstract Fisetin, as a natural dietary flavonoid, exhibits multiple biological activities such as anti-inflammatory, anti-oxidant, and anti-tumorigenic activities. Previous studies have indicated that fisetin has potential renal protective effects in many animal models of kidney disease. However, the effect of fisetin on unilateral ureteral obstruction (UUO)-induced renal interstitial fibrosis (RIF) remains largely unknown. In our present study, we found that fisetin attenuated UUO-induced kidney injury by decreasing fibrotic lesion and the accumulation of extracellular matrix (ECM). The results showed that fisetin could effectively block macrophage-to-myofibroblast transition (MMT) in the kidneys of UUO mice in vivo and in transforming growth factor-β1(TGFb1)-stimulated bone marrow-derived macrophages (BMDM) in vitro. Molecular docking was employed to explore the interactions between fisetin and Src (a key mediator in MMT). The results indicated that fisetin could form hydrogen bonds and hydrophobic interactions with Src, thus binding effectively in the active pocket of Src and exhibiting strong affinity. Further in vivo and in vitro investigation demonstrated that fisetin inhibited activity of Src and subsequently lowered the phosphorylation levels of epidermal growth factor receptor (EGFR) at Tyr845, ERK1/2 and Smad3. In conclusion, this study revealed the mechanism by which fisetin blocked the progression of MMT by inhibiting the activationof Src, thus alleviating UUO-induced RIF. Therefore, fisetin might be a potential therapeutic agent for preventing and alleviating renal fibrosis.