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.

Public Health Relevance

Non-Steroid Anti-Inflammatory Drugs (NSAIDs) are widely used analgesics that alleviate pain and inflammation by inhibiting cyclooxygenase. In recent years, COX-2 inhibitors have dominated the prescription market for NSAIDs but are unfortunately associated with cardiovascular consequences. mPGES-1 is a newly characterized enzyme that couples with COX-2 to mediate the pain and inflammatory response. In light of the toxicities of COX-2 inhibitors, mPGES-1 has received a great attention for serving as an alternative target for the next generation of analgesics. In the current application, we try to study whether mPGES-1 has a physiological role in regulation of fluid volume and blood pressure. New information resulted from this study will help understand the safety profile of mPGES-1 inhibitors. On the other hand, the new information from this study will help understand the fundamental mechanism of how blood pressure is regulated and will eventually help develop more effective and safer therapeutic approaches for management of hypertension.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001034-03
Application #
8398952
Study Section
Nephrology (NEPH)
Project Start
2011-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
Indirect Cost
Name
VA Salt Lake City Healthcare System
Department
Type
DUNS #
009094756
City
Salt Lake City
State
UT
Country
United States
Zip Code
84148