Urolithin A attenuates renal fibrosis by inhibiting TGF-β1/Smad and MAPK signaling pathways

• UA administration ameliorated UUO-induced impairment of renal, evidenced by improved the histopathological abnormalities and abnormal renal function. • UA treatment decreased macrophage infiltration and proinflammatory cytokine gene expression. • UA also attenuated the EMT progression. • UA possessed protective effects on renal fibrosis by inhibiting TGF-β1/Smad and MAPK signaling pathways in vivo and in vitro. Urolithin A (UA) is a bioavailable product of the metabolism of ellagitannins by the gut microbiota, and UA has anti-inflammatory and antioxidant activities. In this study, we investigated whether UA exerted an anti-renal fibrosis effect in a rat model of unilateral ureteral obstruction (UUO) and HK-2 cells treated with TGF-β1. In vivo, UA treatment significantly ameliorated UUO-induced renal tissue impairment and decreased macrophage infiltration and proinflammatory cytokine expression. UA attenuated epithelial-mesenchymal transition (EMT) progression by regulating the expression of E-cadherin and α-SMA. Moreover, UA treatment significantly decreased the levels of TGF-β1, p-Smad2/3, and p-P38/JNK/ERK but increased the level of Smad7. In vitro, UA treatment inhibited TGF-β1-induced HK-2 cell fibrosis and proliferation. Furthermore, UA treatment also led to a reduction in the expression of TGF-β1, p-Smad3, and p-P38/JNK/ERK, which was accompanied by an increase in the expression of Smad7. These results demonstrate that UA exerts protective effects on renal fibrosis by inhibiting the TGF-β1/Smad and MAPK signaling pathways.