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Am J Physiol Renal Physiol 287: F152-F159, 2004. First published March 9, 2004; doi:10.1152/ajprenal.00287.2003
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Inhibition of nNOS expression in the macula densa by COX-2-derived prostaglandin E2

Alex Paliege,1 Diane Mizel,1 Carmen Medina,2 Anita Pasumarthy,1 Yuning G. Huang,1 Sebastian Bachmann,3 Josephine P. Briggs,1 Jurgen B. Schnermann,1 and Tianxin Yang1,2

1National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; 3Department of Anatomy, University of Berlin, 13353 Berlin, Germany; and 2Division of Nephrology, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, Utah 84148

Submitted 18 August 2003 ; accepted in final form 13 February 2004

It is well established that cyclooxygenase-2 (COX-2) and the neuronal form of nitric oxide synthase (nNOS) are coexpressed in macula densa cells and that the expression of both enzymes is stimulated in a number of high-renin states. To further explore the role of nNOS and COX-2 in renin secretion, we determined plasma renin activity in mice deficient in nNOS or COX-2. Plasma renin activity was significantly reduced in nNOS –/– mice on a mixed genetic background and in COX-2 –/– mice on either BALB/c or C57/BL6 congenic backgrounds. In additional studies, we accumulated evidence to show an inhibitory influence of PGE2 on nNOS expression. In a cultured macula densa cell line, PGE2 significantly reduced nNOS mRNA expression, as quantified by real-time RT-PCR. In COX-2 –/– mice, nNOS mRNA expression in the kidney, determined by real-time RT-PCR, was upregulated throughout the postnatal periods, ranging from postnatal day (PND) 3 to PND 60. The induction of nNOS protein expression and NOS activity in COX-2 –/– mice was localized to macula densa cells using immunohistochemistry and NADPH-diaphorase staining methods, respectively. Therefore, these findings reveal that the absence of either COX-2 or nNOS is associated with suppressed renin secretion. Furthermore, the inhibitory effect of PGE2 on nNOS mRNA expression indicates a novel interaction between NO and prostaglandin-mediated pathways of renin regulation.

juxtaglomerular apparatus; cyclooxygenase-2; neuronal nitric oxide synthase; real-time reverse transcriptase-polymerase chain reaction; plasma renin activity


Address for reprint requests and other correspondence: T. Yang, Univ. of Utah and Veterans Affairs Medical Center, Bldg 2, Research Service (151 E), 500 Foothill Drive, Salt Lake City, UT 84148 (E-mail: tianxin.yang{at}hsc.utah.edu).




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