Relaxin inhibits renal interstitial fibrosis and promotes fatty acid metabolism after UUO via the AMPK/PGC1α signaling pathway.

Abstract

Renal tubulointerstitial fibrosis, as the common final pathological outcome of almost all progressive chronic kidney diseases (CKD), is challenging to reverse. Although CKD remains incurable, reversal or amelioration of renal fibrosis is beneficial to retard CKD progression. In this study, based on our in vitro and in vivo studies, we found that relaxin, a human hormone with promising renal protection effects, was closely related to ameliorating tubular injury and reversing tubulointerstitial fibrosis in the obstructed kidney in the mouse model of unilateral ureteral obstruction (UUO). Downregulation of relaxin was accompanied by the development of tubulointerstitial fibrosis and tubular epithelial fatty acid oxidation (FAO) disorder. Furthermore, overexpression of relaxin significantly alleviated, whereas knockdown of relaxin extremely aggravated the process of renal interstitial fibrosis following UUO and FAO disorder in mouse tubular epithelial cells (mTECs). Mechanistically, AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC1α) pathway was validated as a downstream pathway of relaxin, which participated in the regulation of renal interstitial fibrosis. Our findings suggest that upregulation of relaxin positively alleviated renal tubulointerstitial fibrosis in UUO-induced CKD via AMPK-PGC1α axis, which gives insight into novel therapeutic and diagnostic targets of CKD.