Tonic stimulation of renin gene expression by nitric oxide is counteracted by tonic inhibition through angiotensin II.

Abstract

This study was designed to examine the possible involvement of prostaglandins and nitric oxide (NO) in the renin stimulatory effect ofangiotensin 11 (AngII) antagonists. To this end, plasma renin activities (PRAs) and renal renin mRNA levels were assayed in rats that were treated with the Angconverting enzyme inhibitor ramipril or with the AnglI AT1-receptor antagonist losartan. Ramipril and losartan increased PRA values from 7.5 + 1.6 to 86 ± 6 and 78 ± 22 ng of AngI per h per ml and renin mRNA levels from 112 ± 9% to 391 + 20%o and 317 ± 10%o, respectively. Inhibition of prostaglandin formation with indomethacin did not influence basal or ramiprilaffected PRA. Basal renin mRNA levels also were unchanged by indomethacin, while increases in renin mRNA levels after ramipril treatment were slightly reduced by indomethacin. Inhibition of NO synthase by nitro-L-arginine methyl ester (L-NAME) reduced PRA values to 3.2 ± 0.9, 34 ± 13, and 12.1 ± 2.7 ng of AngI per h per ml in control, ramipril-treated, and losartan-treated animals, respectively. Renin mRNA levels were reduced to 77 + 14% under basal conditions and ramipril-and losartan-induced increases in renin mRNA levels were completely blunted after addition of L-NAME. The AngIH antagonists, furthermore, induced an upstream recruitment of reninexpressing cells in the renal afferent arterioles, which was also blunted by L-NAME. These findings suggest that renin mRNA levels are tonically increased by NO and that the action of NO is counteracted by AngII.One of the most prominent in vivo effects of angiotensin (Ang)-converting enzyme (ACE) inhibitors is a marked stimulation of renin secretion and renin gene expression in the kidneys (1-5). Since ANGII is known as a negative feedback regulator of renin secretion and of renin gene expression (6, 7), it is thought that the renin stimulatory effects of ACE inhibitors are related to the inhibition of AnglI formation and consequently to the lowering of circulating and tissue AnglI levels (8).There is evidence that several in vivo effects of ACE inhibitors are not, as originally thought, due to the inhibition of AnglI formation but to the inhibition of kinin degradation (9-12). Inhibition of kinin degradation results in elevated tissue levels of autacoids such as prostaglandins and nitric oxide (NO), the formation of which is stimulated by kinins (11)(12)(13)(14). Although NO is reported to inhibit the renin system (15-17), contradictory findings suggest that NO stimulates the renin system (18-25) and also that prostaglandins stimulate the renin system (for review, see ref. 26). With such a stimulatory effect of NO and prostaglandins on the renin system, it is possible that the renin stimulatory effect of ACE inhibitors could be related to an enhanced formation of prostaglandins and NO.To investigate the mode of action of ACE inhibitors on the renin system, we studied renin release and renin mRNA levels in the kidneys of conscious rats that were treated with the ACE inhibitor ramipril (27) or with the Angll AT1-rec...

Interaction of Nitric Oxide and the Renin Angiotensin System in Renal Hypertensive Rats.

“…Moreover, NO may also mediate the tachyphylactic response seen with administered Ang II because acute NO blockade greatly increased the duration of Ang 11-in duced aortic (12) and afferent arteriolar constriction (9). It has been also reported that NO stimulated renin secre tion from isolated rat kidney (13,14), and this finding has been further supported by Schricker et al (15), who sug gested that renin mRNA levels are tonically increased by NO and that the action of NO is counteracted by Ang II (15), although contradictory findings suggest that NO in hibits the renin system (16). All of these observations suggest that NO interacts with the renin angiotensin sys tem, with NO serving as a counterregulatory influence on the vascular actions of Ang II.…”

Role of cGMP-kinase II in the control of renin secretion and renin expression.

“…Linearization with HindIII and in vitro transcription with SP6 RNA polymerase yielded a 248-bp fragment. Hybridization, RNase digestion, phenol/chloroform extraction, and acrylamide electrophoresis are described in detail elsewhere (14).…”

“…␤ -actin mRNA was used as a standard RNA for controlling the quality of the RNA preparation. Total RNA (1 g) was hybridized under the conditions described previously (14).…”

“…A review of the effects of factors elevating cGMP levels in JG cells, such as endothelium-derived nitric oxide (NO) or atrial natriuretic peptide, reveals a scatter of contradictory results. Thus, NO has been designated both a stimulator (6)(7)(8)(9)(10)(11)(12)(13)(14)(15) and an inhibitor of renin secretion (16)(17)(18)(19)(20)(21) in vivo and in vitro. Similar contradictory data-stimulation (22-24) and inhibition (25)(26)(27)(28) of renin secretion-have been obtained for atrial natriuretic peptide.…”

Towards understanding the kallikrein-kinin system: insights from measurement of kinin peptides

“…Kinin peptide administration increases renin secretion (59,60), possibly mediated by increased nitric oxide formation (61), and icatibant is reported to decrease plasma renin levels in anaesthetized rabbits (62), suggesting that endogenous kinin peptides may tonically stimulate renin secretion. Moreover, the location of B 2 receptors in the kidney is predominantly in the renal tubules, vascular endothelium, and renomedullary interstitial cells of the renal medulla (63), locations appropriate for the modification of renin secretion, possibly by modifying sodium delivery to the macula densa.…”