The long term objective of my lab is to understand the molecular basis of mechanotransduction. This includes the 1) identification of components of mechanosensitive ion channel complexes in sensory neurons and vascular smooth muscle cells, 2) regulation of mechanosensitive ion channel expression by physical and hormonal factors and 3) involvement in cardiovascular pathophysiology (hypertension, autonomic dysfunction). The current proposal will address a highly novel area of research: role of ENaC proteins as mechanosensors in vascular smooth muscle. Hypertension induced renal injury has multiple causes including hormonal and autocrine factors and pressure. Pressure-induced, or myogenic, constriction of renal vessels protects the kidney from pressure related injury. The molecular mechanism underlying mechanotransduction of the pressure stimulus is unknown. The hypothesis underlying this proposal is that beta and/or gamma ENaC proteins are components of mechanosensitive ion channel complexes in vascular smooth muscle cells. Pressure induced vascular tension activates mechanosensitive channels containing beta and gamma ENaC leading to sodium and calcium influx and myogenic constriction. Since myogenic constriction protects the kidney from end-organ damage, we further hypothesize that loss of beta ENaC expression will prevent myogenic constriction and predispose the kidney to pressure induced injury. The goals of this proposal are to determine if beta ENaC protein is required for 1) myogenic constriction, and 2) pressure activated sodium and calcium ion transients, 3) renal autoregulation, and 4) renal protection from pressure induced injury, renal interlobar artery segments. To assess the importance of beta ENaC in these responses, we have developed a double transgenic mouse model where beta ENaC is silenced in a tissue- and time-selective manner. Results from this proposal will help define the molecular mechanism of myogenic constriction and provide a better understanding of pressure induced end organ damage. ? ? ?
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