Genetic deletion of COX-2 prevents increased renin expression in response to ACE inhibition

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, W ang 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, Fishm an MC, Beierwaltes WH, and Carretero OA. Hypertension 29: 297-302, 1997; Tr aynor 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 deletion s of the COX-2 gene in order to investigate further the potential role of C OX-2 in mediation of the renin-angiotensin system (RAS). Age-matched wild-t ype (+/+), heterozygotes (+/-), and homozygous null mice (-/-) were adminis tered the angiotensin-converting enzyme inhibitor (ACEI), captopril, for 7 days. ACEI failed to significantly increase plasma renin activity, renal re nin 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 affer ent arteriole. In contrast, there was minimal recruitment of renin-expressi ng cells in the more proximal afferent arteriole of the -/- mice. In summar y, these results indicate that ACEI-mediated increases in renal renin produ ction were defective in COX-2 knockout (K/O) mice and provide further indic ation that MD COX-2 is an important mediator of the renin-angiotensin syste m.