This is a competitive renewal of a 3-year pilot project to identify the mechanisms by which renal arteries upregulate L-type Ca 2+ (CaL) channels during systemic hypertension, a critical adaptive response that prevents pressure-induced damage of the renal capillary beds. During the first two years of funding, we have documented a positive relationship between elevated blood pressure and an increased expression of the pore-forming alpha1c subunit of CaL channels in renovascular smooth muscle cells (SMCs) from two rat models of hypertension. Importantly, this increase in alpha1c subunit expression was associated with an increased CaL channel current and Ca2+-dependent tone in the SMCs of the affected arteries. In the last 6 months, we initiated the characterization of a renal SMC culture model that will be suitable for identifying mechanisms that induce the expression of alpha1c subunits, including membrane depolarization of SMC membranes. The SMCs express both alpha1c and ancillary beta1-4subunits through passage 5 as assessed by RT-PCR and Western blot, and profoundly upregulate alpha1c subunits in response to KCl-induced depolarization. Based on these key preliminary data, we will pursue specific aims directed toward identifying: (a) the molecular composition of CaL channels in renovascular SMCs, (b) the cellular pathways that mediate the upregulation of alpha1c and beta subunits in response to membrane depolarization, (c) the role of accessory beta1-4subunits in affecting targeting/trafficking of the alpa1C subunit to the plasma membrane and (d) a disease-specific profile of CaL. channel expression and composition in renal arteries of hypertensive rats. Identifying the mechanisms that upregulate CaL. channels in vascular SMCs exposed to high blood pressure will help set the stage for developing new ion channel-based strategies to reduce abnormal Ca2+-dependent tone in vasospastic diseases including essential hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Experimental Cardiovascular Sciences Study Section (ECS)
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Barouch, Winifred
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University of Arkansas for Medical Sciences
Schools of Medicine
Little Rock
United States
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