Resveratrol suppresses the myofibroblastic phenotype and fibrosis formation in kidneys via proliferation‐related signalling pathways

Abstract

Background and Purpose: Renal fibrosis acts as the common pathway leading to the development of end-stage renal disease. Previous studies have shown that resveratrol has anti-fibrotic activity, but its potential molecular mechanisms of action are not well understood. Experimental Approach: The anti-fibrotic effects of resveratrol were assayed in a rat model of unilateral ureteral obstruction (UUO) in vivo and in fibroblasts and tubular epithelial cells (TECs) stimulated by TGF-β1 in vitro. Gene and protein expression levels were analysed by PCR, Western blotting, and immunohistochemical staining. Key Results: Resveratrol inhibits the myofibroblastic phenotype and fibrosis formation in UUO kidneys by targeting fibroblast-myofibroblast differentiation (FMD) and epithelial-mesenchymal transition (EMT). The anti-fibrotic effects of resveratrol correlated with decreased proliferation of TECs in the interstitium and tubules, resulting in suppressed activity of the proliferation-related signalling pathways, including that of the MAPK, PI3K/Akt, Wnt/β-catenin, and JAK2/STAT3 pathways. Resveratrol treatment suppressed TGF-β1-induced FMD and the expression of the myofibroblastic phenotype in fibroblasts in vitro by antagonizing the activation of proliferation-related signalling. Similarly, TGF-β1-mediated overactivation of the proliferation-related signalling in TECs induced EMT, and the myofibroblastic phenotype was suppressed by resveratrol. The anti-fibrotic and anti-proliferative effects of resveratrol were associated with the inactivation of Smad2/3 signalling and resulted in a partial reversal of FMD and EMT and the inhibition of the myofibroblastic phenotype. Conclusions and Implications:Resveratrol suppresses the myofibroblastic phenotype and fibrosis formation in vivo and in vitro via proliferation-related pathways, making it a potential therapeutic agent for preventing renal fibrosis.

Role of SIK1 in the transition of acute kidney injury into chronic kidney disease

“…Multiple intracellular signal transduction pathways are involved in the expression and activation of EMT and renal fibrosis, including TGF-β signaling pathway, PI3K/AKT pathway, Src pathway, MAPK pathway, and WNT signaling pathway [36][37][38][39][40][41]. Among these, WNT/ β-catenin signaling pathway, the most classic WNT pathway, was widely studied.…”

Resveratrol Modulates Transforming Growth Factor-Beta (TGF-β) Signaling Pathway for Disease Therapy: A New Insight into Its Pharmacological Activities

“…In RF treatment, fibroblast–myofibroblast differentiation (FMD), EMT, and the proliferation of tubular epithelial cells (TECs) should be targeted. The administration of Res can disrupt Smad2/3 activation by TGF-β and consequently suppress the proliferation of TECs, FMD, and EMT [ 158 ]. Increasing evidence demonstrates that EMT may be involved in renal fibrogenesis, and its activation can facilitate the development of RF [ 159 , 160 , 161 , 162 ].…”

The Anti-Dysenteric Drug Fraxetin Enhances Anti-Tumor Efficacy of Gemcitabine and Suppresses Pancreatic Cancer Development by Antagonizing STAT3 Activation

“…Immuno uorescence staining was performed according to our previous report [19]. Firstly, PANC-1 and Patu8988 cells treated with fraxetin were grown on glass coverslips for 24 h, and then xed with 4% formaldehyde for 30 min.…”