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