PM2.5-induced hypertension via renal GRK4/Nedd4L/ENaC axis: epigenetic and post-translational mechanisms.

BACKGROUND

Ambient fine particulate matter (PM2.5) is a major environmental risk factor for hypertension, yet the renal sodium-handling mechanisms remain incompletely understood. This study investigates the role of G protein-coupled receptor kinase 4 (GRK4) and its downstream signalling axis in PM2.5-induced hypertensive pathogenesis.

METHODS

Male Sprague-Dawley rats were exposed to PM2.5 (10 or 40 mg/kg) via intratracheal instillation for 12 weeks. Hemodynamic parameters, renal function, and molecular alterations were analysed using immunohistochemistry, Western blot, qPCR, and co-immunoprecipitation. GRK4 expression was manipulated via lentiviral vectors to validate its role in blood pressure regulation.

RESULTS

PM2.5 exposure induced dose-dependent hypertension, renal dysfunction, and sodium retention. Mechanistically, PM2.5 upregulated renal GRK4 expression through promoter hypomethylation, enhancing its interaction with Nedd4L (a ubiquitin ligase). Phosphorylated Nedd4L (p-Nedd4L) reduced epithelial sodium channel (ENaC) ubiquitination, leading to ENaC accumulation and sodium reabsorption. GRK4 overexpression exacerbated hypertension and sodium retention, whereas GRK4 knockdown attenuated these effects.

CONCLUSION

This study identifies a novel signalling axis-GRK4/Nedd4L/ENaC-in PM2.5-induced hypertension, highlighting epigenetic and post-translational regulatory mechanisms. These findings provide mechanistic insights into environmentally mediated hypertensive pathogenesis and suggest potential therapeutic targets for PM2.5-related cardiovascular diseases.