Basic Clin Pharmacol Toxicol. 2026 Oct;139(4):e70299. doi: 10.1111/bcpt.70299.
ABSTRACT
Vascular smooth muscle cells (VSMCs) are essential for maintaining arterial wall integrity, with their associated apoptosis critically involved in cardiovascular diseases. Intracellular chloride anion (Cl-) dysregulation is closely linked to apoptosis. However, the underlying mechanism via chloride-sensitive kinases remains unclear. Here, we show that hypotonic stimulation activates volume-regulated chloride channels (VRCCs) and induces the phosphorylation of the chloride-sensitive kinase WNK1. Activated WNK1 protects VSMCs against H2O2-induced apoptosis by maintaining the Bcl-2/Bax balance, preserving mitochondrial membrane potential and inhibiting caspase-9/3 activation. These findings uncover a novel protective role of WNK1 in VRCC-mediated Cl- signalling and provide new perspectives for targeting chloride-sensitive kinases in the treatment of hypertension and related cardiovascular diseases.
PMID:42675813 | DOI:10.1111/bcpt.70299