P110 Inhibits DRP1/FIS1-Mediated Mitochondrial Fission to Alleviate Uric Acid-Induced Apoptosis in HK-2 Cells

Hyperuricemic nephropathy is associated with mitochondrial dysfunction. Dynamin-related protein 1 (DRP1), a key regulator of mitochondrial fission, is activated under stress and translocates to the mitochondria, where it interacts with adapter proteins such as mitochondrial fission 1 protein (FIS1), thereby promoting excessive mitochondrial fission and apoptosis. Recent research has shown that inhibiting the DRP1/FIS1 interaction can reduce cellular injury in various disease models; however, its role in hyperuricemic nephropathy is unclear.

An in vitro model of hyperuricemic nephropathy was established by treating human renal tubular epithelial cells with uric acid (UA). Reverse transcription quantitative PCR and western blotting, and enzyme-linked immunosorbent assays were used to quantify the mRNA and protein levels of the target molecules. A specific peptide inhibitor, P110, was used to disrupt the binding between DRP1 and FIS1. Co-immunoprecipitation (Co-IP) was performed to confirm the interactions between DRP1 and FIS1. Cell viability was assessed using propidium iodide staining and the Cell Counting Kit-8 assay.

UA significantly upregulated DRP1 expression, activated DRP1, and promoted mitochondrial translocation. P110 inhibited DRP1/FIS1 binding, preventing DRP1 UA-induced mitochondrial translocation. Excessive mitochondrial fission, reactive oxygen species generation, release of inflammatory factors, and apoptosis were significantly alleviated. In addition, inhibition of DRP1 mitochondrial translocation decreased the expression of apoptosis-related markers and apoptosis.

The overactivation of DRP1 is crucial for UA-induced renal tubular epithelial cell injury. P110 exerts a cytoprotective effect by inhibiting the DRP1/FIS1 interaction and modulating the mitochondrial apoptotic pathway. This study proposes a possible target for therapeutic intervention in the treatment of hyperuricemic nephropathy.