HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 295/4/F1082    most recent 90316.2008v1 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 (2) Citing Articles via Google Scholar Google Scholar Articles by Abdullah, H. I. Articles by Ferreri, N. R. Search for Related Content PubMed PubMed Citation Articles by Abdullah, H. I. Articles by Ferreri, N. R.

Calcium-sensing receptor signaling pathways in medullary thick ascending limb cells mediate COX-2-derived PGE₂ production: functional significance

Department of Pharmacology, New York Medical College, Valhalla, New York

Submitted 16 May 2008 ; accepted in final form 31 July 2008

We determined the functional implications of calcium-sensing receptor (CaR)-dependent, G_q- and G_i-coupled signaling cascades, which work in a coordinated manner to regulate activity of nuclear factor of activated T cells and tumor necrosis factor (TNF)- gene transcription that cause expression of cyclooxygenase (COX)-2-derived prostaglandin E₂ (PGE₂) synthesis by rat medullary thick ascending limb cells (mTAL). Interruption of G_q, G_i, protein kinase C (PKC), or calcineurin (CaN) activities abolished CaR-mediated COX-2 expression and PGE₂ synthesis. We tested the hypothesis that these pathways contribute to the effects of CaR activation on ion transport in mTAL cells. Ouabain-sensitive O₂ consumption, an in vitro correlate of ion transport in the mTAL, was inhibited by 70% in cells treated for 6 h with extracellular Ca²⁺ (1.2 mM), an effect prevented in mTAL cells transiently transfected with a dominant negative CaR overexpression construct (R796W), indicating that the effect was initiated by stimulation of the CaR. Pretreatment with the COX-2-selective inhibitor, NS-398 (1 µM), reversed CaR-activated decreases in ouabain-sensitive O₂ consumption by 60%, but did not alter basal levels of ouabain-sensitive O₂ consumption. Similarly, inhibition of either G_q, G_i, PKC, or CaN, which are components of the mechanism associated with CaR-stimulated COX-2-derived PGE₂ synthesis, reversed the inhibitory effects of CaR on O₂ consumption without affecting basal O₂ consumption. Our findings identified signaling elements required for CaR-mediated TNF production that are integral components regulating mTAL function via a mechanism involving COX-2 expression and PGE₂ production.

tumor necrosis factor; loop of Henle; nuclear factor of activated T cells; oxygen consumption

This article has been cited by other articles:

				V. E. Torres Type II Calcimimetics and Polycystic Kidney Disease: Unanswered Questions J. Am. Soc. Nephrol., July 1, 2009; 20(7): 1421 - 1425. [Full Text] [PDF]

				S. Hao, H. Zhao, Z. Darzynkiewicz, S. Battula, and N. R. Ferreri Expression and function of NFAT5 in medullary thick ascending limb (mTAL) cells Am J Physiol Renal Physiol, June 1, 2009; 296(6): F1494 - F1503. [Abstract] [Full Text] [PDF]