Direct pharmacological targeting of Piezo1 by Paeoniflorin: a novel therapeutic approach for renal fibrosis

BACKGROUND: Renal fibrosis-characterized by microcirculatory disturbances and endothelial-mesenchymal transition (EndMT)-is a major pathological feature of chronic kidney disease (CKD) and remains a significant therapeutic challenge. The mechanosensitive ion channel Piezo1 plays a pivotal role in endothelial mechanotransduction and has been implicated in fibrogenesis, yet specific pharmacological interventions targeting Piezo1 are lacking. METHODS: We evaluated the renoprotective effects of paeoniflorin (PF), a bioactive monoterpene glycoside, in 5/6 nephrectomy-induced chronic renal failure (CRF) rats and diabetic kidney disease (DKD) db/db mice. PF-Piezo1 interactions were characterized using molecular docking, surface plasmon resonance (SPR), and functional assays. In vitro studies employing models of matrix stiffness, endothelial-fibroblast crosstalk, and HIF-1α inhibition were performed to elucidate the underlying mechanisms. RESULTS: influx and attenuating stiffness-induced EndMT. PF restored the expression of endothelial markers including VE-cadherin and eNOS, and suppressed HIF-1α-mediated upregulation of Vimentin and TGF-β1. Moreover, co-culture experiments demonstrated that PF disrupted endothelial-derived TGF-β1 paracrine signaling, reducing fibroblast activation and extracellular matrix deposition. Notably, Piezo1 knockdown or HIF-1α inhibition recapitulated the dual effects of PF on endothelial restoration and fibrosis suppression. CONCLUSIONS: /HIF-1α axis, thereby mitigating renal fibrosis. By interrupting pathological endothelial-fibroblast communication and restoring microvascular integrity, PF represents a promising mechanotherapeutic strategy for CKD.