Loss of Chloride Channel 6 (CLC-6) Affects Vascular Smooth Muscle Contractility and Arterial Stiffness via Alterations to Golgi Calcium Stores. Issue 2 (February 2021)

• Record Type: Journal Article
• Authors: Klemens, Christine A.; Chulkov, Evgeny G.; Wu, Jing; Hye Khan, Md Abdul; Levchenko, Vladislav; Flister, Michael J.; Imig, John D.; Kriegel, Alison J.; Palygin, Oleg; Staruschenko, Alexander
• Is Part Of: Hypertension. Volume 77:Issue 2(2021)
• Publication Date: 2021-02
• Subjects: blood pressure -- electrophysiology -- homeostasis -- hypertension -- muscle, smooth, vascular; Hypertension -- Periodicals; Hypertension -- Treatment -- Periodicals; 616.132005
• DOI: 10.1161/HYPERTENSIONAHA.120.16589
• Languages: English
• ISSNs: 0194-911X

Abstract

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. Abstract : Supplemental Digital Content is available in the text.