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Am J Physiol Regul Integr Comp Physiol 283: R638-R646, 2002; doi:10.1152/ajpregu.00150.2002
0363-6119/02 $5.00
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Vol. 283, Issue 3, R638-R646, September 2002

Prostaglandins that increase renin production in response to ACE inhibition are not derived from cyclooxygenase-1

Hui-Fang Cheng1, Sue-Wan Wang1, Ming-Zhi Zhang2, James A. McKanna2, Richard Breyer1, and Raymond C. Harris1

George M. O'Brien Kidney Disease Center, Division of Nephrology, Departments of 1 Medicine and 2 Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

It is well known that nonselective, nonsteroidal anti-inflammatory drugs inhibit renal renin production. Our previous studies indicated that angiotensin-converting enzyme inhibitor (ACEI)-mediated renin increases were absent in rats treated with a cyclooxygenase (COX)-2-selective inhibitor and in COX-2 -/- mice. The current study examined further whether COX-1 is also involved in mediating ACEI-induced renin production. Because renin increases are mediated by cAMP, we also examined whether increased renin is mediated by the prostaglandin E2 receptor EP2 subtype, which is coupled to Gs and increases cAMP. Therefore, we investigated if genetic deletion of COX-1 or EP2 prevents increased ACEI-induced renin expression. Age- and gender-matched wild-type (+/+) and homozygous null mice (-/-) were administered captopril for 7 days, and plasma and renal renin levels and renal renin mRNA expression were measured. There were no significant differences in the basal level of renal renin activity from plasma or renal tissue in COX-1 +/+ and -/- mice. Captopril administration increased renin equally [plasma renin activity (PRA): +/+ 9.3 ± 2.2 vs. 50.1 ± 10.9; -/- 13.7 ± 1.5 vs. 43.9 ± 6.6 ng ANG I · ml-1 · h-1; renal renin concentration: +/+ 11.8 ± 1.7 vs. 35.3 ± 3.9; -/- 13.0 ± 3.0 vs. 27.8 ± 2.7 ng ANG I · mg protein-1 · h-1; n = 6; P < 0.05 with or without captopril]. ACEI also increased renin mRNA expression (+/+ 2.4 ± 0.2; -/- 2.1 ± 0.2 fold control; n = 6-10; P < 0.05). Captopril led to similar increases in EP2 -/- compared with +/+. The COX-2 inhibitor SC-58236 blocked ACEI-induced elevation in renal renin concentration in EP2 null mice (+/+ 24.7 ± 1.7 vs. 9.8 ± 0.4; -/- 21.1 ± 3.2 vs. 9.3 ± 0.4 ng ANG I · mg protein-1 · h-1; n = 5) as well as in COX-1 -/- mice (SC-58236-treated PRA: +/+ 7.3 ± 0.6; -/- 8.0 ± 0.9 ng ANG I · ml-1 · h-1; renal renin: +/+ 9.1 ± 0.9; -/- 9.6 ± 0.5 ng ANG I · mg protein-1 · h-1; n = 6-7; P < 0.05 compared with no treatment). Immunohistochemical analysis of renin expression confirmed the above results. This study provides definitive evidence that metabolites of COX-2 rather than COX-1 mediate ACEI-induced renin increases. The persistent response in EP2 nulls suggests involvement of prostaglandin E2 receptor subtype 4 and/or prostacyclin receptor (IP).

angiotensin-converting enzyme inhibitor; cyclooxygenase-2 -/-; prostaglandin E2 receptor subtype 2


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