Kurarinone protects against renal injury and fibrosis after unilateral ureteral obstruction through enhancement of the Nrf-2 signaling pathway

Background

Chronic kidney disease (CKD) is an epidemic with higher cardiovascular risk, and this pathology involves renal injury and fibrosis. Kurarinone (KAR) has anti-inflammatory and anticancer effects, which can regulate immune responses and macrophage polarization. This study aimed to investigate the effect of KAR on model-induced unilateral ureteral obstruction (UUO) renal injury and fibrosis.

Methods

We constructed the rat model of sham, UUO, UUO + low (10 IU/kg), medium (20 IU/kg) and high (40 IU/kg) doses of KAR groups in vivo, and we analyzed pathologic changes and expression of vimentin and α-smooth muscle actin (α-SMA), cluster of differentiation group 206, F4/80, FN, Snail1, Kim1, small mother against decapentaplegic (Smad) 3 and transforming growth factor-beta [TGF-β1]. Furthermore, we developed the HK-2 cell fibrosis model using TGF-β1 (5 ng/ml) for 24 h in vitro. We used real-time quantitative polymerase chain reaction, Western blotting, and immunohistochemistry to detect α-SMA protein, TGF-β1, Smad3, and p-Smad3 levels in renal tissues. We examine protein levels of the Keap1/Nrf2 pathway using the Nrf-2 inhibitor, ML385, and downregulation of Nrf-2 expression using Western blotting.

Results

Our results revealed that KAR improved renal function and downregulated α-SMA protein. Furthermore, KAR induced the polarization of M2 macrophages. KAR improved fibrosis by inhibiting the TGF-β1/Smad3 pathway. KAR inhibited renal fibrosis and inflammation by activating the Keap1/Nrf2 pathway in vivo and in vitro.

Conclusions

KAR inhibited renal fibrosis and inflammation through the Keap1/Nrf-2 pathway, indicating that it may become a small molecular drug for chronic kidney disease.