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

Run Li; Jikai Xia; Chunru Shi; Keying Zhang; Yilun Qu; Guosen He; Zhangning Fu; Lingchen Deng; Ran Liu; Xu Wang; Guangyan Cai; Zheyi Dong; Ping Li; Xiangmei Chen; Quan Hong

doi:10.1016/j.jare.2025.07.015

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

J Adv Res. 2025 Jul 11:S2090-1232(25)00540-5. doi: 10.1016/j.jare.2025.07.015. Online ahead of print.

Authors

Run Li¹, Jikai Xia², Chunru Shi³, Keying Zhang⁴, Yilun Qu⁴, Guosen He², Zhangning Fu⁴, Lingchen Deng¹, Ran Liu⁴, Xu Wang⁴, Guangyan Cai⁴, Zheyi Dong⁵, Ping Li⁶, Xiangmei Chen⁷, Quan Hong⁸

Affiliations

¹ School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Preventionand Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Beijing 100853, China.
² Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Preventionand Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Beijing 100853, China; Guangdong Pharmaceutical University, Guangzhou 510006, China.
³ Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
⁴ Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Preventionand Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Beijing 100853, China.
⁵ Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Preventionand Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Beijing 100853, China. Electronic address: shengdai26@163.com.
⁶ Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Preventionand Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Beijing 100853, China. Electronic address: liping.8@163.com.
⁷ School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Preventionand Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Beijing 100853, China. Electronic address: xmchen301@126.com.
⁸ Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Preventionand Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Beijing 100853, China. Electronic address: hongquan@301hospital.com.cn.

PMID: 40653265
DOI: 10.1016/j.jare.2025.07.015

Abstract

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: PF treatment preserved renal function, reduced glomerulosclerosis, and ameliorated microvascular rarefaction in both CRF and DKD. Molecular docking and SPR analyses revealed that PF binds Piezo1 with high affinity, thereby inhibiting Yoda1-induced Ca2⁺ 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 angiogenesis and fibrosis suppression.

Conclusions: Our findings indicate that PF exerts renoprotective effects by targeting the Piezo1/Ca²⁺/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.

Keywords: EndMT; HIF-1α; Microcirculation; Paeoniflorin; Piezo1; Renal fibrosis.