Intrarenal dopaminergic system regulates renin expression.
Dopamine is a major regulator of proximal tubule salt reabsorption and is a modulator of renin release. Dopamine has been reported to stimulate renin release in vitro through activation of D1-like receptors. However, previous studies investigating dopamine regulation of renin release in vivo have provided contradictory results, indicating stimulation, inhibition, or no effect. We have reported previously that macula densa cyclooxygenase-2 (COX-2) is suppressed by dopamine. Because macula densa COX-2 stimulates renal renin expression, our current studies investigated dopamine regulation of renal renin release and synthesis in vivo. Acute treatment with a D1-like receptor agonist, fenoldopam, significantly inhibited renin release, as did acute inhibition of proximal tubule salt reabsorption with acetazolamide. In catechol-O-methyl transferase knockout (COMT(-/-)) mice, which have increased kidney dopamine levels because of deletion of the major intrarenal dopamine metabolizing enzyme, there was attenuation in response to a low-salt diet of the increases of renal cortical COX-2 and renin expression and renin release. A high-salt diet led to significant decreases in renal renin expression but much less significant decreases in COMT(-/-) mice than wild type mice, resulting in higher renal renin expression in COMT(-/-) mice. In high salt-treated wild-type mice or COX-2 knockout mice on a normal salt diet, fenoldopam stimulated renal renin expression. These results suggest that dopamine predominantly inhibits renal renin expression and release by inhibiting macula densa COX-2, but suppression of renal cortical COX-2 activity reveals a contrasting effect of dopamine to stimulate renal renin expression through activation of D1-like receptors.
Zhang
Ming-Zhi
MZ
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
Yao
Bing
B
Fang
Xiaofeng
X
Wang
Suwan
S
Smith
James P
JP
Harris
Raymond C
RC
D000818:Animals; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D005260:Female; D018818:Fenoldopam / Q000494:pharmacology; D007686:Kidney Tubules, Distal / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism; D012083:Renin / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology; D012965:Sodium Chloride / Q000494:pharmacology
D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; D012965:Sodium Chloride; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D002394:Catechol O-Methyltransferase; D012083:Renin; D018818:Fenoldopam; D004298:Dopamine