Nitric oxide regulates renal cortical cyclooxygenase-2 expression

We have previously shown that cyclooxygenase-2 (COX-2) is localized to the cortical thick ascending limb of the loop of Henle (cTALH)/macula densa of the rat kidney, and expression increases in response to low-salt diet and/o r angiotensin-converting enzyme (ACE) inhibition. Because of the localizati on of neuronal nitric oxide synthase (nNOS) to macula densa and surrounding cTALH, the present study investigated the role of nitric oxide (NO) in the regulation of COX-2 expression. For in vivo studies, rats were fed a norma l diet, low-salt diet or low-salt diet combined with the ACE inhibitor capt opril. In each group, one-half of them were treated with the nNOS inhibitor s 7-nitroinidazole (7-NI) or S-methylthiocitrulline. Both of these NOS inhi bitors inhibited increases in COX-2 mRNA and immunoreactive protein in resp onse to low salt and low salt+captopril. For in vitro studies, COX-2 expres sion was studied in primary cultures of rabbit cTALH cells immunodisssected with Tamm-Horsfall antibody. Basal COX-2 immunoreactivity expression was s timulated by S-nitroso-N-acetyl-penicillamine (SNAP), an NO donor, and intr acellular cGMP concentration. The cultured cells expressed immunoreactive n NOS, and 7-NI inhibited basal COX-2 immunoreactivity expression, which coul d be partially overcome by cGMP. In summary, these studies indicate that NO is a mediator of increased renal cortical COX-2 expression seen in volume depletion and suggest important interactions between the NO and COX-2 syste ms in the regulation of arteriolar tone and the renin-angiotensin system by the macula densa.