Targeted inhibition of TGF-β type I receptor by AZ12601011 protects against kidney fibrosis

Renal fibrosis, a common feature of chronic kidney disease, causes the progressive loss of renal function, in which TGF-beta 1 plays a critical role. In this study, we found that expression levels of TGF-beta 1 and its receptor 1 (TGF-beta R1) were both significantly increased in obstructive fibrosis kidneys. AZ12601011 is a small molecular inhibitor of TGF-beta R1; however, its therapeutic potential for renal fibrosis remains unclear. During the experiments, AZ12601011 was applied to various models of renal fibrosis followed by unilateral ureteral obstruction (UUO) and ischemia/reperfusion (I/R) in vivo, in addition to renal tubular epithelial cells (TECs) challenged by hypoxia/ reoxygenation (H/R) and TGF-beta 1 in vitro. Our results revealed that AZ12601011 ameliorated renal injuries and fibrosis shown by PAS, HE, and Masson staining, which was consistent with the decrease in Col-1 and alpha-SMA expression in the kidneys from UUO and I/R mice. Similarly, in vitro data showed that AZ12601011 inhibited the induction of Col-1 and alpha-SMA in both TECs treated with TGF-beta 1 and H/R. In addition, the results of cellular thermal shift assay (CETSA), molecular docking, and western bolt indicated that AZ12601011 could directly bind to TGF-beta R1 and block activation of the downstream Smad3. Taken together, our findings suggest that AZ12601011 can attenuate renal fibrosis by blocking the TGF-beta/Smad3 signaling pathway and it might serve as a promising clinical candidate in the fight against fibrotic kidney diseases.

Automated summary

This study found that the expression levels of TGF-beta 1 and its receptor 1 were increased in obstructive fibrosis kidneys. The results showed that AZ12601011 could ameliorate renal injuries and fibrosis by blocking the TGF-beta/Smad3 signaling pathway.