Published online before print November 9, 2006, doi: 10.1161/01.RES.0000251306.40546.08
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Submitted on June 15, 2006
Revised on October 13, 2006
Accepted on October 20, 2006
Deletion of Microsomal Prostaglandin E Synthase-1 Increases Sensitivity to Salt Loading and Angiotensin II Infusion
Zhanjun Jia ;
From the Department of Internal Medicine (Z.J., A.Z., H.Z., T.Y.), University of Utah and Veterans Affairs Medical Center, Salt Lake City; Cellular Biology and Anatomy (Z.D.), Medical College of Georgia, Augusta; and Medical Research Service (Z.D.), Veterans Affairs Medical Center, Augusta, Ga.
* To whom correspondence should be addressed. E-mail: tianxin.yang{at}hsc.utah.edu.
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-/- 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 E2 and nitrate/nitrite were remarkably increased in wild-type animals but not in mPGES-1-/- mice. The changes of urinary cGMP paralleled that of urinary nitrate/nitrite. mPGES-1-/- 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 E2 release. These findings have revealed a mPGES-1/prostaglandin E2/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.
Key words: mPGES-1 • mean arterial pressure • prostaglandin E2, nitric oxide • angiotensin II • and collecting duct.
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