A dual role of AcSDKP in chronic kidney disease: Targeting pericyte-driven fibrosis and vascular repair via VEGF/FGFR1 while eliciting a compensatory FGFR1 upregulation in apoptotic tubular cells

Abstract

Background Renal interstitial fibrosis and peritubular capillary (PTC) rarefaction drive the progression of chronic kidney disease (CKD). While N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous anti-fibrotic peptide, its specific effects on pericyte-endothelial crosstalk and tubular epithelial survival remain controversial. Methods We employed a self-controlled unilateral aristolochic acid (AA)-induced CKD mouse model to evaluate the time-sensitive efficacy of AcSDKP. In vitro, primary murine pericytes, human tubular epithelial cells (HK-2), and endothelial cells were utilized. Functional mechanisms were dissected using VEGF ELISA, RNA-sequencing, and targeted FGFR1 siRNA knockdown. Results In vitro, AcSDKP potently suppressed TGF-β1-induced pericyte-to-myofibroblast transition (PMT) and robustly restored pericyte-derived VEGF secretion, thereby rescuing endothelial tubulogenesis. In vivo, early AcSDKP intervention (Week 3) significantly mitigated fibrosis, preserved capillary integrity, and improved systemic renal function (BUN/SCr), whereas late intervention (Week 4) was less effective. Transcriptomics identified the VEGF/FGFR1 axis as a primary target of AcSDKP. However, in AA-injured HK-2 cells, AcSDKP paradoxically exacerbated apoptosis despite upregulating FGFR1. Subsequent siRNA knockdown revealed that silencing FGFR1 drastically worsened apoptosis, proving that endogenous FGFR1 upregulation is a compensatory survival response. AcSDKP’s epithelial toxicity is fundamentally FGFR1-independent, driven instead by its concurrent inhibition of the Akt survival pathway. Conclusion AcSDKP exerts a compartment-specific dual role in CKD. It is a potent vascular protector that halts PMT and promotes VEGF-driven endothelial repair, but acts as a pro-apoptotic stressor in severely damaged tubules. Its clinical translation necessitates early-stage intervention and optimized delivery strategies to maximize vascular benefits while mitigating epithelial toxicity.