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

Christine A Klemens, Evgeny G Chulkov, Jing Wu, Md Abdul Hye Khan, Vladislav Levchenko, Michael J Flister, John D Imig, Alison J Kriegel, Oleg Palygin, Alexander Staruschenko

Hypertension (Dallas, Tex. : 1979) 2021 Feb

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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.

Citation

Christine A Klemens, Evgeny G Chulkov, Jing Wu, Md Abdul Hye Khan, Vladislav Levchenko, Michael J Flister, John D Imig, Alison J Kriegel, Oleg Palygin, Alexander Staruschenko. Loss of Chloride Channel 6 (CLC-6) Affects Vascular Smooth Muscle Contractility and Arterial Stiffness via Alterations to Golgi Calcium Stores. Hypertension (Dallas, Tex. : 1979). 2021 Feb;77(2):582-593