ClC-5 knockout mitigates angiotensin II-induced hypertension and endothelial dysfunction

Abstract

Aims

Impairment of nitric oxide (NO) production is a major cause of endothelial dysfunction and hypertension. ClC-5 Cl⁻ channel is abundantly expressed in the vascular endothelium. However, it remains unclear how it regulates endothelial function.

Materials and methods

In this study, we used mice with a knockout of the Clcn5 gene encoding ClC-5 protein globally or specifically in vascular endothelium.

Key findings

ClC-5 knockout globally or specifically in vascular endothelium mitigates the elevation of mean blood pressure and impairment of endothelial dysfunction induced by Angiotensin II. This effect is mediated by the reversal of the impairment of NO production after the stimulation of the Akt/endothelial nitric oxide synthase (eNOS) signal pathway. Application of a low Cl⁻ extracellular solution onto endothelial cells stimulates a ClC-5-dependent current and lowered intracellular Cl⁻ concentration, which activates with-no-lysine (K)-1 (WNK1), a Cl⁻-sensitive kinase. Silencing ClC-5 or WNK1 expression rescues the impairment of endothelial NO production induced by a low Cl⁻ solution. In contrast, overexpression of ClC-5 or WNK1 led to the opposite results. WNK1, found to be associated with Rho-specific guanine nucleotide dissociation inhibitor (RhoGDI), increases RhoA activity, and thereby inhibits the endothelial Akt/eNOS signaling pathway.

Significance

ClC-5 knockout mitigates Ang II-induced hypertension and endothelial dysfunction by promoting NO production via regulating WNK1/RhoA/Akt/eNOS signaling pathway. The results may be useful for developing novel treatments of endothelial dysfunction associated-diseases.