Faculty Collaboration Database

Loss of Chloride Channel 6 (CLC-6) Affects Vascular Smooth Muscle Contractility and Arterial Stiffness via Alterations to Golgi Calcium Stores. Hypertension 2021 Feb;77(2):582-593

Date

01/05/2021

Pubmed ID

33390052

Pubmed Central ID

PMC7856014

DOI

10.1161/HYPERTENSIONAHA.120.16589

Scopus ID

2-s2.0-85100070512 (requires institutional sign-in at Scopus site)   7 Citations

Abstract

Genome-wide association studies have found a number of potential genes involved in blood pressure regulation; however, the functional role of many of these candidates has yet to be established. One such candidate gene is CLCN6, which encodes the transmembrane protein, chloride channel 6 (ClC-6). Although the CLCN6 locus has been widely associated with human blood pressure regulation, the mechanistic role of ClC-6 in blood pressure homeostasis at the molecular, cellular, and physiological levels is completely unknown. In this study, we demonstrate that rats with a functional knockout of ClC-6 on the Dahl Salt-Sensitive rat background (SS-Clcn6) have lower diastolic but not systolic blood pressures. The effect of diastolic blood pressure attenuation was independent of dietary salt exposure in knockout animals. Moreover, SS-Clcn6 rats are protected from hypertension-induced cardiac hypertrophy and arterial stiffening; however, they have impaired vasodilation and dysregulated intracellular calcium handling. ClC-6 is highly expressed in vascular smooth muscle cells where it is targeted to the Golgi apparatus. Using bilayer electrophysiology, we provide evidence that recombinant human ClC-6 protein can function as a channel. Last, we demonstrate that loss of ClC-6 function reduces Golgi calcium stores, which may play a previously unidentified role in vascular contraction and relaxation signaling in vascular smooth muscle cells. Collectively, these data indicate that ClC-6 may modulate blood pressure by regulating Golgi calcium reserves, which in turn contribute to vascular smooth muscle function.

Author List

Klemens CA, Chulkov EG, Wu J, Hye Khan MA, Levchenko V, Flister MJ, Imig JD, Kriegel AJ, Palygin O, Staruschenko A

Authors

Evgenii Chulkov Postdoctoral Fellow in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Alison J. Kriegel PhD Associate Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blood Pressure
Calcium
Chloride Channels
Golgi Apparatus
Muscle Contraction
Muscle, Smooth, Vascular
Myocytes, Smooth Muscle
Rats
Rats, Inbred Dahl
Sodium, Dietary
Vascular Stiffness