LAUSR

Background: Low serum chloride (Cl−) level is considered an independent predictor of cardiovascular mortality associated with chronic hypertension. However, the underlying mechanisms are unknown. ClC-5, a member of the Cl− channel family, is sensitive to changes in intracellular and extracellular Cl− concentration and conducts outwardly rectifying Cl− currents. The aims of this study were to determine if ClC-5 is regulated by low extracellular Cl−, clarify its putative roles in hypertension-induced cerebrovascular remodeling, and elucidate the associated underlying mechanisms. Methods: Whole-cell patch technique, intracellular Cl− concentration measurements, flow cytometry, Western blot, Clcn5 knockdown (Clcn5−/y), and adenovirus-mediated ClC-5 overexpression mice, 2-kidney, 2-clip, and angiotensin II infusion–induced hypertensive models were used. Results: We found that low extracellular Cl− evoked a ClC-5–dependent Cl− current that was abolished by ClC-5 depletion in basilar artery smooth muscle cells (BASMCs). ClC-5 was upregulated in the arterial tissues of rats and patients with hypertension. Low Cl−–induced current and ClC-5 protein expression positively correlated with basilar artery remodeling during hypertension. ClC-5 knockdown ameliorated hypertension-induced cerebrovascular remodeling and smooth muscle cell proliferation, whereas ClC-5 overexpression mice exhibited the opposite phenotype. ClC-5–dependent Cl− efflux induced by low extracellular Cl− activated WNK1 (lysine-deficient protein kinase 1) which, in turn, activated AKT (protein kinase B), and culminated in BASMC proliferation and vascular remodeling. Conclusions: ClC-5 mediates low extracellular Cl–induced Cl− currents in BASMCs and regulates hypertension-induced cerebrovascular remodeling by promoting BASMC proliferation via the WNK1/AKT signaling pathway.