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(Circulation Research. 2006;99:1243.)
© 2006 American Heart Association, Inc.

Integrative Physiology

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

Zhanjun Jia, Aihua Zhang, Hui Zhang, Zheng Dong, Tianxin Yang

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.

Correspondence to Tianxin Yang, MD, PhD, University of Utah and VA Medical Center, 30N 1900 E, Rm 4C224, Salt Lake City, UT 84132. 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 • collecting duct

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