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This Article Full Text Full Text (PDF) All Versions of this Article: 293/6/F1805    most recent 00307.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Ge, Y. Articles by Kohan, D. E. Search for Related Content PubMed PubMed Citation Articles by Ge, Y. Articles by Kohan, D. E.

Role of prostaglandins in collecting duct-derived endothelin-1 regulation of blood pressure and water excretion

Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah

Submitted 5 July 2007 ; accepted in final form 2 October 2007

Collecting duct (CD)-derived endothelin-1 (ET-1) exerts natriuretic, diuretic, and hypotensive effects. In vitro studies have implicated cyclooxygenase (COX) metabolites, and particularly PGE₂, as important mediators of CD ET-1 effects. However, it is unknown whether PGE₂ mediates CD-derived ET-1 actions in vivo. To test this, CD ET-1 knockout (KO) and control mice were studied. During normal salt and water intake, urinary PGE₂ excretion was unexpectedly increased in CD ET-1 KO mice compared with controls. Salt loading markedly increased urinary PGE₂ excretion in both groups of mice; however, the levels remained relatively higher in KO animals. Acutely isolated inner medullary collecting duct (IMCD) from KO mice also had increased PGE₂ production. The increased IMCD PGE₂ was COX-2 dependent, since NS-398 blocked all PGE₂ production. However, increased CD ET-1 KO COX-2 protein or mRNA could not be detected in inner medulla or IMCD, respectively. Inner medullary COX-1 mRNA and protein levels and IMCD COX-1 mRNA levels were unaffected by Na intake or CD ET-1 KO. KO mice on a normal or high-Na diet had elevated blood pressure compared with controls; this difference was not altered by indomethacin or NS-398 treatment. However, indomethacin or NS-398 did increase urine osmolality and reduce urine volume in KO, but not control, animals. In summary, IMCD COX-2-dependent PGE₂ production is increased in CD ET-1 KO mice, indicating that CD-derived ET-1 is not a primary regulator of IMCD PGE₂. Furthermore, the increased PGE₂ in CD ET-1 KO mice partly compensates for loss of ET-1 with respect to maintaining urinary water excretion, but not in blood pressure control.

cyclooxygenase; inner medullary; sodium

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