Zhang_2025_Int.J.Biol.Sci_21_3901

Renal fibrosis is a characteristic of the progression of various chronic kidney diseases (CKD) to end-stage renal disease (ESRD). The renin-angiotensin system (RAS) is key to renal pathology. A better understanding of its regulatory mechanisms at the molecular level may lead to solutions for clinical CKD. Interestingly, our cohort study observed a positive correlation between epithelial dipeptidyl peptidase-IV (DPP4) levels and clinical CKD progression. Consistently, DPP4 was significantly increased in the unilateral ureteral obstruction (UUO) injured kidney in vivo and human epithelial kidney HK-2 cells under Ang II stimulation in vitro. Unexpectedly, kidney-specific deletion of DPP4 effectively ameliorated UUO and ischemia/reperfusion (I/R)-driven renal fibrosis in vivo. Mechanistically, we reveal that DPP4 serves as a novel inhibitor of the Ang(1-7)/MasR axis and an inducer of the AT1R axis by directly binding to ACE2 at the protein level. More importantly, targeting DPP4 with pharmaceutical inhibitor linagliptin effectively restored anti-fibrotic pathway of RAS, thereby blocking the CKD progression of I/R-injured kidney in vivo. Therefore, epithelial DPP4 may represent a precise therapeutic target to enhance the anti-fibrotic activity of RAS for CKD treatment in the clinic.