Paracrine Control of Blood Pressure by Renal Intercalated Cells

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 DESCRIPTION (provided by applicant): The collecting duct (CD) is the terminal segment of the nephron serving as the final determinant of sodium content in the ultrafiltrate. As such, the CD plays a key role in overall control of sodium excretion and blood pressure. CD epithelium consists of two major cell lineages, principal cells (PCs) and intercalated cells (ICs). In the traditional view, PCs are primarily responsible for sodium transport, whereas the main role of the ICs is regulating urinary acidification. However, recent studies have identified more complex functions for ICs including substantive sodium and chloride reabsorption. Here, we propose an additional role for ICs as a source of paracrine mediators inducing natriuresis and promoting resistance to hypertension. Specifically, in our preliminary studies, we discovered a pathway linked to AT1 angiotensin receptors (AT1R) in CD epithelial cells, most likely ICs, triggering expression of cyclo-oxygenase (COX)-2, generating vasodilator prostaglandins, and attenuating the development of hypertension. Along with classical second messengers linked to G-protein activation, ligand binding to GPCRs, including the AT1R, can trigger ß-arrestins to activate alternative signaling pathways with distinct physiological effects. In this regard, we find that AT1R-dependent stimulation of COX-2 in isolated medullary CDs requires ß-arrestin 2. Based on our preliminary work, we have formulated two hypotheses: (1) Expression of COX-2 and production of prostanoids by ICs is a general protective mechanism providing resistance to hypertension by preserving renal blood flow and promoting natriuresis; and (2) Activation of COX-2 by AT1R in the CD is driven by ß-arrestin signaling, independent of canonical G-protein pathways. We will test our hypotheses through the following Specific Aims: (1) Characterize the capacity of COX-2 in intercalated cells to ameliorate the severity of hypertension. (2) Define the mechanism of natriuresis triggered by AT1 receptors in intercalated cells. (3) Define the contribution of ß- arrestin to the induction of COX2 in ICs. Through these studies, we will characterize molecular control of a novel pathway linked to resistance to hypertension and attempt to uncover strategies to manipulate its activity.