Urotensin II Exerts Pressor Effects By Stimulating Renin And Aldosterone Synthase Gene Expression

Abstract

We investigated the in vivo pressor effects of the potent vasoconstrictor Urotensin II (UII). We randomized normotensive Sprague-Dawley rats into 4 groups that received a 7-day UII infusion (cases) or vehicle (controls). Group 1 received normal sodium intake; Group 2 underwent unilateral nephrectomy and salt loading; Group 3 received spironolactone, besides unilateral nephrectomy and salt loading; Group 4 only received spironolactone. UII raised BP transiently after a lag phase of 12-36 hours in Group 1, and progressively over the week in Group 2. Spironolactone did not affect blood pressure, but abolished both pressor effects of UII in Group 3, and left blood pressure unaffected in Group 4. UII increased by 7-fold the renal expression of renin in Group 2, increased aldosterone synthase expression in the adrenocortical zona glomerulosa, and prevented the blunting of renin expression induced by high salt. UII raises BP transiently when sodium intake and renal function are normal, but progressively in salt-loaded uninephrectomized rats. Moreover, it increases aldosterone synthase and counteracts the suppression of renin induced by salt loading. This novel action of UII in the regulation of renin and aldosterone synthesis could play a role in several clinical conditions where UII levels are up-regulated.

Figure 1

Study design. 15 weeks-old male Sprague-Dawley rats were divided into 4 groups of 12 animals divided into 6 cases that received a 7-days infusion of urotensin II and 6 controls receiving vehicle. Npx = unilateral nephrectomy; Na = sodium; UII = urotensin II, 600 pmol/kg/h; Spiro = spironolactone, 20 mg/kg/day. See text for details.

Figure 2

BP profiles. Systolic and diastolic BP changes at beat-to-beat radio-telemetry recording in rats of Group 1 receiving UII (panel A, normal sodium diet), in unilaterally nephrectomized rats of Group 2 receiving UII and high (2%) NaCl diet (panel B, High Sodium + Uninephrectomy), in rats of Group 3 similarly treated but receiving also spironolactone (panel C, High Sodium + Uninephrectomy + Spironolactone), and in rats of Group 4 that received UII and spironolactone (panel D, Normal Sodium + Spironolactone). Mean ± SD; n = 6 per group. *p < 0.001 day 1 vs day 0; **p < 0.001 day 7 vs day 0; ^#p < 0.01 UII infused rats vs vehicle infused rats.

Figure 3

UII infusion increased renin gene expression in the kidney. Box and whisker plot showing the fold changes (in log₁₀ scale) of renin gene expression in the kidney (measured by ∆∆CT method using PBGD mRNA as a reference), relative to vehicle-infused (control) rats. UII induced a marked increase in rats with normal salt intake and renal function (Group 1), as well as in uninephrectomized rats undergoing 2% sodium loading (Groups 2-3). Renin expression was blunted in uninephrectomized rats undergoing 2% sodium loading that did not receive UII (controls). Please note that spironolactone increased renin in Group 3 and in Group 4 as compared to uninephrectomized and salt loaded animals. Median and 95% CI, n = 6 per group, one-way ANOVA and post-hoc Bonferroni’s test.

Figure 4

UII infusion markedly increased Cyp11b2 gene expression in the zona glomerulosa. Box and whisker plot showing the fold change relative to measurements in vehicle-infused (control) rats in Cyp11b2 gene expression in the adrenocortical zona glomerulosa. UII increased Cyp11b2 expression in rats with normal salt intake and normal renal function (Group 1), and in uni-nephrectomized rats undergoing 2% sodium loading (Group 2-3). Cyp11b2 gene expression was blunted in uni-nephrectomized rats undergoing 2% sodium loading. Median (5-95 percentile), n = 6 rats per group, one-way ANOVA and post-hoc Bonferroni’s test.

Figure 5

UII infusion induced aldosterone secretion in the zona glomerulosa. UII infusion increased plasma aldosterone concentration (PAC) in rats with normal salt intake and normal renal function (Group 1), and in uni-nephrectomized rats undergoing 2% sodium loading (Group 2). Mean ± SD; n = 5 per group.

Figure 6

Urotensin II, besides exerting a direct vasoconstrictor effect, enhances the expression of renin in juxtaglomerular (JG) cells and the expression of aldosterone synthase in the adrenocortical zona glomerulosa. Through increased angiotensin (Ang) II formation it further raises the gene expression of aldosterone synthase, thus contributing to increase blood pressure. Under normal salt intake and renal function these pressor effects are counteracted by the escape phenomenon. However, they become evident during salt loading and acutely impaired renal function. Inset: Double immunohistochemistry staining shows renin (red) in the juxta-glomerular (JG) cells of the vascular pole of glomeruli and UT-R (brown) in the in endothelium of glomerular arterioles.