Shizhifang alleviates hyperuricemia -induced renal injury by inhibiting Drp1 and maintaining mitochondrial homeostasis in renal tubular epithelial cells

Abstract

Ethnopharmacological relevance

Shizhifang (SZF), a traditional Chinese herbal formula used at Shanghai Shuguang Hospital for over 20 years, has shown clinical efficacy in lowering serum uric acid (SUA) and protecting renal function.

Aim of the study

To explore the mechanism by which SZF protects against hyperuricemia (HUA)-induced renal tubular epithelial cell injury, focusing on mitochondrial dysfunction mediated by Drp1.

Materials and methods

RNA-seq was performed on HK2 cells to identify affected pathways. HUA rat and mouse models were used to assess renal function, oxidative stress, inflammation, and mitophagy. Key interventions included SZF, a Drp1 inhibitor, and autophagy modulators. In vitro, Drp1 knockdown HK2 cells were used to evaluate ROS, mitochondrial membrane potential (MMP), and proteins involved in mitochondrial dynamics and mitophagy.

Results

SZF significantly reduced SUA, improved renal function, suppressed ROS and inflammation, and alleviated mitochondrial damage. RNA-seq revealed enrichment of ROS and mitophagy pathways. SZF and Drp1 inhibition restored MMP, reduced fission and mitophagy, and enhanced mitochondrial fusion. Combined SZF and Drp1 siRNA treatment showed superior efficacy.

Conclusions

SZF mitigates HUA-induced renal injury by inhibiting Drp1-mediated mitochondrial fission and mitophagy, promoting mitochondrial fusion, and reducing oxidative stress. These findings reveal a novel mitochondrial mechanism for SZF's reno-protective effect.