Renal effects induced by prolonged mPGES1 inhibition

Area of Science:

• Nephrology
• Pharmacology
• Physiology

Background:

• Membrane-bound prostaglandin E synthase 1 (mPGES1) plays a role in renal function regulation.
• Previous studies on mPGES1's renal effects used deficiency models or expression changes, not prolonged inhibition.
• The impact of sustained mPGES1 inhibition on renal function under varying sodium intake remains unclear.

Purpose of the Study:

• To investigate the renal effects of a selective mPGES1 inhibitor, PF-458, in dogs.
• To assess these effects during normal sodium intake (NSI) and low sodium intake (LSI) over 7 days.

Main Methods:

• Conscious, chronically instrumented dogs were administered PF-458 (2.4 or 9.6 mg·kg(-1)·day(-1)) under NSI or LSI conditions.
• Renal blood flow (RBF), glomerular filtration rate (GFR), and urinary excretory function were monitored.
• Levels of PGE2, 6-keto-PGF1α, plasma renin activity, aldosterone, and thromboxane B2 were measured.

Main Results:

• PF-458 selectively inhibited mPGES1, decreasing PGE2 and increasing 6-keto-PGF1α.
• In LSI dogs, the higher dose of PF-458 reduced RBF but not GFR; no hemodynamic changes occurred in NSI dogs.
• No significant changes in renal excretory function or related hormones/mediators were observed in either NSI or LSI dogs.

Conclusions:

• mPGES1 is involved in regulating RBF during low sodium intake in dogs.
• Renal effects of mPGES1 inhibition are modulated by a compensatory increase in prostacyclin (PGI2).
• Prolonged mPGES1 inhibition appears to have fewer renal side effects than NSAIDs or COX-2 inhibitors.