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Articles in PresS, published online ahead of print July 16, 2002
Am J Physiol Renal Physiol, 10.1152/ajprenal.00108.2002
Submitted on March 21, 2002
Accepted on July 2, 2002
1 Department of Pharmacology, New York Medical College, Valhalla, NY, USA
* To whom correspondence should be addressed. E-mail: nick_ferreri{at}nymc.edu.
Medullary thick ascending limb (mTAL) cells in primary culture express calcium sensing receptor (CaR), a G-protein coupled receptor that senses changes in extracellular calcium concentration ([Ca2+]o) resulting in increases of intracellular calcium ([Ca2+]i) and protein kinase C (PKC) activity. Exposure of mTAL cells to either extracellular Ca2+ (Ca2+o) or the CaR-selective agonist, poly-L-arginine increased tumor necrosis factor-alpha (TNF) synthesis. Moreover, the response to Ca2+o was enhanced in mTAL cells transfected with a CaR overexpression vector. Transfection of mTAL cells with a TNF promoter construct revealed an increase in reporter gene activity following exposure of the cells to Ca2+o suggesting that intracellular signaling pathways initiated via activation of CaR contribute to TNF synthesis by a mechanism that involves transcription of the TNF gene. Neutralization of TNF activity with an anti-TNF antibody attenuated calcium-mediated increases in cyclooxygenase-2 (COX-2) protein expression and PGE2 synthesis suggesting that TNF exerts an autocrine effect in the mTAL, which contributes to COX-2-mediated PGE2 production. Preincubation with the PKC inhibitor bisindolylmaleimide I inhibited calcium-mediated TNF production. Significant inhibition of COX-2 protein expression and PGE2 synthesis also was observed when cells were challenged with Ca2+o in the presence of bisindolylmaleimide I. The data suggest that increases in TNF production subsequent to activation of CaR may be the basis of an important renal mechanism that regulates salt and water excretion.
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