Inhibition of nNOS expression in the macula densa by COX-2-derived prostaglandin E(2).
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 PGE(2) on nNOS expression. In a cultured macula densa cell line, PGE(2) 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 PGE(2) on nNOS mRNA expression indicates a novel interaction between NO and prostaglandin-mediated pathways of renin regulation.
Paliege
Alex
A
National Institute of Diabetes and Kidney Disease, National Institutes of Health, Bethesda, MD 20892, USA.
Mizel
Diane
D
Medina
Carmen
C
Pasumarthy
Anita
A
Huang
Yuning G
YG
Bachmann
Sebastian
S
Briggs
Josephine P
JP
Schnermann
Jurgen B
JB
Yang
Tianxin
T
D000818:Animals; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000494:pharmacology*; D005786:Gene Expression Regulation; D007527:Isoenzymes / Q000494:pharmacology*; D007668:Kidney / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics; D052248:Nitric Oxide Synthase Type I; D011451:Prostaglandin-Endoperoxide Synthases / Q000494:pharmacology*; D012083:Renin / Q000097:blood / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology
D007527:Isoenzymes; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D012083:Renin; D015232:Dinoprostone