The isoform NHE3 of the Na+/H+ exchanger plays a crucial role in sodium reabsorption in the proximal tubules and, consequently in the regulation of extracellular volume and blood pressure. A large body of evidence indicates that the redistribution of this transporter between the microdomains of the proximal tubule brush border membrane, namely, the microvillar and intermicrovillar domains, may represent one of the most important downstream effector of pressure natriuresis, i.e., the capacity of the kidneys to alter the urinary flow and sodium excretion in response to changes in the renal perfusion pressure. Angiotensin II (AngII) mediates sodium and water retention and this predominantly occurs through stimulation of NHE3 in the renal proximal tubule. It is well established Ang II regulates NHE3 activity via receptor AT1 and subsequent activation of heteromeric G protein signaling. However, preliminary results from our research group have showed that AT1 receptor biased agonists, i.e., compounds that selectively activate the beta-arrestin-dependent signaling cascade and G protein-independent, inhibit NHE3 activity. Additionally, recent studies have suggest that the AT1 receptor may act as a mecanotransducer of shear stress and that beta-arrestin plays a crucial role in mecanotransduction. In light of the above, we propose to thoroughly analyze the effects of the AT1 receptor- beta-arrestin signaling pathway in the renal proximal tubule. More specifically, we intend to define the downstream signaling components of the AT1-beta arrestin pathway and the molecular mechanisms by which beta-arrestin inhibits NHE3 activity in the renal proximal tubule using both in vitro and in vivo models. Additionally, we will test the hypothesis that activation of the AT1-beta-arretin pathway induced by shear stress either in vitro or in vivo (by increasing the renal perfusion pressures) may participate in the pressure natriuresis mechanism by triggering a mecanotransduction cascate that ultimately leads to NHE3 redistribution from the microvilli to intermicrovilli and increased sodium excretion. The renin-angiotensin system plays a pivotal role in the pathogenesis of hypertension, heart failure and diabetic nephropathy. From the pathway triggered by the AT1 receptor independent of G proteins arises an unprecedented opportunity to discover novel drug candidates for the treatment of these diseases.
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