mPGES-1/EP1 in volume regulation

Va Salt Lake City Healthcare System, Salt Lake City UT

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Abstract

DESCRIPTION (provided by applicant): Summary: The kidney plays a major role in the regulation of extracellular fluid volume (ECFV) and blood + + pressure (BP) via adjustment of urinary Na excretion in alignment with Na intake. Despite intensive + investigation, the molecular mechanism of renal handing of Na and water balance is still imperfectly understood. A large body of evidence demonstrates that PGE2 is an important regulator of renal function + due to its natriuretic and diuretic properties. In isolated microperfused renal tubules, PGE2 inhibits Na and water transport. Moreover, the inhibition of prostanoid synthesis with Non-Steroid Anti-inflammatory Drugs (NSAIDs) or COX-2 inhibitors is associated with cardiovascular consequences, including hypertension and edema formation. Microsomal prostaglandin E synthase-1 (mPGES-1) has been characterized as the only isomerase processing the in vivo PGES activity and is critically involved in the pain and inflammatory responses. In recent years, mPGES-1 has received a great attention due to the promise for serving as a novel target for anti-inflammatory drugs. The lesson from COX-2 inhibitors has prompted a thorough examination of the role of mPGES-1 in physiological processes. Our published studies demonstrate that mPGES-1 KO mice exhibit impaired natriuretic/diuretic responses to salt loading and also fail to undergo aldosterone (Aldo) escape. The phenotype was recapitulated by EP1 antagonism. We hypothesize that renal mPGES-1/ EP1 pathway responds to a rise in renal perfusion pressure (RPP) + during ECFV expansion and elicits natriuresis through inhibition of renal Na transport thereby + attenuating Na retention and hypertension. We propose to define the role of mPGES-1- and EP1 receptors under two different volume expansion states induced by Aldo infusion and high salt loading. Major experimental approaches involve the production and analysis of mice with renal cell-deletion of mPGES-1 and EP1 as well as the examination of RPP as a regulator of renal PGE2 synthesis. There are 3 specific aims: 1) to investigate the influence of systemic mPGES-1 deletion on volume regulation, 2) to investigate the influence of site-specific mPGES-1 inhibition on volume regulation, and 3) to investigate the role of EP1 in volume regulation. New information resulted from this proposal will help define PGE cascades in the control of ECFV.