Deletion of Microsomal Prostaglandin E Synthase-1 Increases Sensitivity to Salt Loading and Angiotensin II Infusion

Abstract

Abstract-Microsomal prostaglandin E synthase-1 (mPGES-1), a membrane-associated protein, is critically involved in the inflammatory response and may be involved in physiological processes as well. The present study examined the role of mPGES-1 in regulation of sodium balance and blood pressure in the settings of salt loading and angiotensin II infusion. mPGES-1 Ϫ/Ϫ mice developed severe and progressive hypertension associated with an inappropriate increase in sodium balance when fed a high-salt diet. These mice exhibited a significantly impaired ability to excrete an acute enteral load of NaCl. Under these 2 settings of salt loading, urinary excretion of prostaglandin E 2 and nitrate/nitrite were remarkably increased in wild-type animals but not in mPGES-1 Ϫ/Ϫ mice. The changes of urinary cGMP paralleled that of urinary nitrate/nitrite. mPGES-1 Ϫ/Ϫ mice exhibited a remarkable inhibition of high salt-induced increase in gene expression of all 3 NO synthase isoforms, whereas these mice had upregulated expression of NO synthase III but not NO synthase I and NO synthase II at basal state. Chronic salt loading remarkably induced mPGES-1 protein expression exclusively in the distal nephron. In primary cultures of CD cells, mPGES-1 expression was significantly increased following exposure to hypertonic NaCl, in parallel with increased prostaglandin E 2 release. These findings have revealed a mPGES-1/prostaglandin E 2 /NO/cGMP pathway that appears to be critically important for salt adaptation. In addition, we provide evidence that mPGES-1 deficiency sensitized the hypertensive effect of angiotensin II. Overall, this study has characterized the natriuretic and antihypertensive role of mPGES-1 that likely contributes to blood pressure homeostasis.

Microsomal Prostaglandin Synthase-1–Derived Prostaglandin E 2 Protects Against Angiotensin II–Induced Hypertension via Inhibition of Oxidative Stress

“…Under baseline conditions, adult mPGES-1 Ϫ/Ϫ mice did not exhibit major cardiovascular or metabolic phenotypes, except a modest reduction of mean arterial pressure (MAP), as described previously. 15 Genotypes were identified by PCR.…”

“…15 Daily MAP was recorded as mean values of 4-hour recordings from 9 AM to 1 PM. After collection of baseline MAP for 3 days, mPGES-1 ϩ/ϩ mice were implanted with an osmotic minipump driving infusion of vehicle or Ang II at 0.35, 0.70, or 2.00 mg/kg per day.…”

“…In support of this notion, we have shown recently that mice lacking mPGES-1 exhibit enhanced sensitivity to chronic Ang II infusion, as well as chronic salt loading. 15 The present study was undertaken to further explore the protective role and mechanism of vascular mPGES-1 in the setting of Ang II infusion.…”

Augmented cyclooxygenase-2 effects on renal function during varying states of angiotensin II

“…In contrast to the diminished vasoconstricting influence suggested by decreased TxA 2 levels (39) and TxA 2 synthase activity (39) during sodium restriction, the role of PGE 2 via augmented microsomal PGE synthase-1 (20) and prostaglandin (EP 4 ) receptor (19) expression is enhanced. Furthermore, macula densa cells have been shown to release PGE 2 in response to low salt (27).…”

Lipid Mediators in Life Science

“…First, Ptges -/-mice develop progressive hypertension with an inappropriate increase in sodium balance when fed a high-salt diet [22], and also exhibit an impaired ability to excrete an acute water load [73]. These observations indicate that mPGES-1-driven PGE 2 is important for renal homeostasis.…”