Targeting DPP9 attenuates podocyte injury by regulating NRF2 antioxidant signaling

Abstract

Introduction Podocyte injury is a critical event in the progression of chronic kidney disease (CKD), with oxidative stress as a central pathogenic mechanism. Despite the efficacy of finerenone in mitigating CKD progression, its precise cytoprotective mechanisms within podocytes remain incompletely defined. This study aimed to elucidate the role of dipeptidyl peptidase 9 (DPP9) in podocyte injury and determine whether finerenone exerts its renoprotective effects via DPP9‐mediated antioxidant effects. Methods Integrated bioinformatic analyses of single‐cell and bulk transcriptomic databases (KIT, NephroSeq) were performed, with validation in renal biopsies from patients with diabetic kidney disease (DKD) and in murine models of DKD and adriamycin‐induced nephropathy. In vitro, immortalized human podocyte (HPC) cells were stimulated with high glucose or adriamycin, with DPP9 knockdown or overexpression. RNA sequencing and immunoprecipitation assays were utilized to explore the underlying molecular mechanisms and protein interactions. Results DPP9 was significantly downregulated in injured podocytes from both human and murine models. DPP9 overexpression activated NRF2‐mediated antioxidant responses, protecting podocytes from injury, whereas DPP9 depletion exacerbated cellular damage. Finerenone upregulated DPP9 protein levels, which subsequently enhanced DPP9-KEAP1 binding and competitively disrupted the NRF2‐KEAP1 interaction, leading to NRF2 stabilization and activation. Consequently, finerenone improved renal function and alleviated pathological damage in vivo. Conclusion This study identifies DPP9 as a critical mediator of podocyte antioxidant defense and establishes that the therapeutic efficacy of finerenone is, at least in part, dependent on the upregulation of DPP9.