Kaempferol ameliorates renal injury by inhibiting Piezo1/HIF-1a/ROS/NLRP3 signaling in chronic kidney disease.

Chronic kidney disease (CKD) has emerged as a growing global health challenge with considerable public health implications. Although renal transplantation remains the only curative treatment for end-stage CKD, traditional Chinese herbal therapy has shown significant therapeutic benefits in its management. Kaempferol (KAE), a biologically active compound present in a wide range of foods and medicinal plants, has been demonstrated to possess antioxidant, anti-inflammatory, and nephroprotective properties. This study aims to elucidate the molecular mechanisms through which KAE exerts its therapeutic effects in CKD. Firstly, a CKD mouse model was established. Additionally, immunofluorescence labeling and western blotting were performed to elucidate the renoprotective mechanisms of KAE. To evaluate intracellular calcium dynamics in VSMCs, we performed dynamic calcium monitoring and patch-clamp electrophysiology. Network pharmacology analysis suggested the involvement of the HIF-1α pathway in KAE's therapeutic effects on CKD. Through molecular docking analysis, it was shown that KAE could bind effectively to the Piezo1 protein. Furthermore, a co-culture system of MOVAS and HK-2 cells were established to validate KAE's suppressive effects on the Piezo1/HIF-1α/ROS/NLRP3 cascade. This study reveals that KAE effectively improved renal function and alleviated renal damage. Both in vivo and in vitro experiments further demonstrated that KAE inhibited glycolytic metabolism and pyroptotic cell death in renal tissues. The accumulated data suggests KAE's clinical potential as a novel CKD therapeutic agent.