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The expression of two isoforms of cyclooxygenase-2 (COX-2) was investigated after subtotal renal ablation in the rat. Results show that selective increases in renal cortical COX-2 mRNA and immunoreactive expression was observed. Aside from the dominant expression of COX-2 in the cortical thick ascending loop of Henle in the region of the macula densa, a detectable COX-2 immunoreactivity was also observed in some glomeruli with high expression in visceral epithelial cells and mesangial cells.

The inducible isoform of cyclooxygenase, COX-2 is the one constitutively expressed in the vas deferens of males. The expression of COX-2 in the vas deferens epithelium is not affected by vasectomy but is significantly inhibited by castration. The reaction catalyzed by cyclooxygenase is the limiting step in the synthesis of prostaglandins. The constitutive expression of one of its isoforms in the vas deferens is suggestive of its role in erectile mechanisms.

Young spontaneously hypertensive rats (SHR) at the start of significant hypertension were observed to have an increased expression of type 1 angiotensin II receptor (AT1R) mRNA and immunoreacive protein compared to age-matched Wistar-Kyoto rats. On the other hand, there were no differences in AT1R in the adult SHR. The increased expression in young SHR was prevented either by angiotension converting enzyme inhibition or exogenous administration of dopamine precursor.

Kidney research shows that genetic expression of enzyme cyclooxygenase (COX-2) occurs under normal physiological conditions. Evidence suggests that COX-2 influences cell differentiation within the kidney. Experiments using Sprague-Dawley and Long-Evans rats are described. Northern analysis techniques are used to demonstrate COX-2 messenger ribonucleic acid levels.

Cheng, Hui-Fang, Jun-Ling Wang, Ming-Zhi Zhang, Su-Wan Wang, James. A. McKanna, and Raymond C. Harris. Genetic deletion of COX-2 prevents increased renin expression in response to ACE inhibition. Am J Physiol Renal Physiol 280: F449-F456, 2001.--Cyclooxygenase-2 (COX-2) is expressed in macula densa (MD) and surrounding cortical thick ascending limb of the loop of Henle (cTALH) and is involved in regulation of renin production. We and others have previously found that selective COX-2 inhibitors can inhibit renal renin production (Cheng HF, Wang JL, Zhang MZ, Miyazaki Y, Ichikawa I, McKanna JA, and Harris RC. J Clin Invest 103: 953-961, 1999; Harding P, Sigmon DH, Alfie ME, Huang PL, Fishman MC, Beierwaltes WH, and Carretero OA. Hypertension 29: 297-302, 1997; Traynor TR, Smart A, Briggs JP, and Schnermann J. Am J Physiol Renal Physiol 277: F706-F710, 1999; Wang JL, Cheng HF, and Harris RC. Hypertension 34: 96-101, 1999). In the present studies, we utilized mice with genetic deletions of the COX-2 gene in order to investigate further the potential role of COX-2 in mediation of the renin-angiotensin system (RAS). Age-matched wild-type (+/+), heterozygotes (+/-), and homozygous null mice (-/-) were administered the angiotensin-converting enzyme inhibitor (ACEI), captopril, for 7 days. ACEI failed to significantly increase plasma renin activity, renal renin mRNA expression, and renal renin activity in (-/-) mice. ACEI increased the number of cells expressing immunoreactive renin in the (+/+) mice both by inducing more juxtaglomerular cells to express immunoreactive renin and by recruiting additional renin-expressing cells in the more proximal afferent arteriole. In contrast, there was minimal recruitment of renin-expressing cells in the more proximal afferent arteriole of the -/- mice. In summary, these results indicate that ACEI-mediated increases in renal renin production were defective in COX-2 knockout (K/O) mice and provide further indication that MD COX-2 is an important mediator of the renin-angiotensin system. macula densa; juxtaglomerular; angiotensin-converting enzyme; cyclooxygenase-2

Nitric oxide regulates renal cortical cyclooxygenase-2 expression. Am J Physiol Renal Physiol 278: F122-F129, 2000.--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/or angiotensin-converting enzyme (ACE) inhibition. Because of the localization 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 normal diet, low-salt diet or low-salt diet combined with the ACE inhibitor captopril. In each group, one-half of them were treated with the nNOS inhibitors 7-nitroinidazole (7-NI) or S-methyl-thiocitrulline. Both of these NOS inhibitors inhibited increases in COX-2 mRNA and immunoreactive protein in response to low salt and low salt+captopril. For in vitro studies, COX-2 expression was studied in primary cultures of rabbit cTALH cells immunodisssected with Tamm-Horsfall antibody. Basal COX-2 immunoreactivity expression was stimulated by S-nitroso-N-acetyl-penicillamine (SNAP), an NO donor, and intracellular cGMP concentration. The cultured cells expressed immunoreactive nNOS, and 7-NI inhibited basal COX-2 immunoreactivity expression, which could 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 systems in the regulation of arteriolar tone and the renin-angiotensin system by the macula densa. cyclooxygenase; nitric oxide synthase; renin; macula densa