Protective effects of SKLB023 on a mouse model of unilateral ureteral obstruction by the modulation of gut microbiota

Renal interstitial fibrosis is the common pathway underlying the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD) and the corresponding therapies are limited. Quantitative and qualitative alterations in gut microbiota are noted in patients with CKD and ESRD. In our previous study, SKLB023 exhibited antifibrotic effects by interfering TGF-β1/Smad3 signaling in obstructive nephropathy. However, it remained unclear that oral administration of SKLB023 drives the alteration of gut microbiota to attenuate renal fibrosis. In the study, the marked inflammation and interstitial fibrosis were found in the kidney tissues of unilateral ureteral obstruction (UUO) mice. While treatment with SKLB023 significantly alleviated renal interstitial fibrosis and reduced serum proinflammatory cytokines TNF-α, IL-6 levels. Importantly, SKLB023 derived the modulation of gut microbiota with the increasing similarity between the composition of gut microbiota in the control and UUO. The number of Turicibacter and Candidatus_Arthromitus was significantly decreased following UUO surgery and recovered by SKLB023, which positively correlated with pro-inflammatory cytokine expression. These results indicated the potential relationship between the antifibrotic benefits of SKLB023 and gut microbiota alteration, which provided new insights into drug therapy via gut microbiota modulation in obstructive nephropathy.