Renal functional responses to selective intrarenal renin inhibition in Cyp1a1-Ren2 transgenic rats with ANG II-dependent malignant hypertension

Abstract

Angiotensin (ANG) II-dependent hypertension is characterized by increases in intrarenal ANG II levels, derangement in renal hemodynamics, and augmented tubular sodium reabsorptive capability. Increased nephron expression of renin-angiotensin system components, such as angiotensinogen by proximal tubule cells and renin by collecting duct principal cells, has been associated with an augmented ability of the kidney to form ANG II in hypertensive states. However, the contribution of de novo intrarenal ANG II production to the development and maintenance of ANG II-dependent hypertension remains unclear. The present study was performed to determine the effects of selective intrarenal renin inhibition on whole kidney hemodynamics and renal excretory function in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension in the absence of the confounding influence of associated reductions in mean arterial pressure (MAP). Male Cyp1a1-Ren2 transgenic rats were induced to develop malignant hypertension, anesthetized, and surgically prepared for intrarenal administration of the direct renin inhibitor aliskiren (0.01 mg/kg). Following acute aliskiren treatment, urine flow and sodium excretion increased (10.5 ± 1.1 to 15.9 ± 1.9 μl/min, P < 0.001; 550 ± 160 to 1,370 ± 320 neq/min, P < 0.001, respectively) and ANG II excretion decreased (120 ± 30 to 63 ± 17 fmol/h, P < 0.05). There were no significant changes in MAP, glomerular filtration rate, estimated renal plasma flow, plasma ANG II levels, or protein excretion. The present findings demonstrate that selective renal renin inhibition elicits diuretic and natriuretic responses in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension. Elevated intraluminal ANG II levels likely act to augment tubular reabsorptive function and, thereby, contribute to the elevated blood pressure in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension.

Fig. 1.

Mean arterial blood pressure in noninduced and hypertensive Cyp1a1-Ren2 rats during control conditions (filled bars) and after intrarenal bolus injection of aliskiren (hatched bars). ***P < 0.001.

Fig. 2.

Glomerular filtration rate in noninduced and hypertensive Cyp1a1-Ren2 rats during control conditions (filled bars) and after intrarenal bolus injection of aliskiren (hatched bars). *P < 0.05.

Fig. 3.

Renal plasma flow in noninduced and hypertensive Cyp1a1-Ren2 rats during control conditions (filled bars) and after intrarenal bolus injection of aliskiren (hatched bars). **P < 0.01.

Fig. 4.

Renal vascular resistance in noninduced and hypertensive Cyp1a1-Ren2 rats during control conditions (filled bars) and after intrarenal bolus injection of aliskiren (hatched bars). **P < 0.01.

Fig. 5.

Urine flow in noninduced and hypertensive Cyp1a1-Ren2 rats during control conditions (filled bars) and after intrarenal bolus injection of aliskiren (hatched bars). *P < 0.05, ***P < 0.001.

Fig. 6.

Urinary sodium excretion in noninduced and hypertensive Cyp1a1-Ren2 rats during control conditions (filled bars) and after intrarenal bolus injection of aliskiren (hatched bars). ***P < 0.001.

Fig. 7.

Fractional sodium excretion in noninduced and hypertensive Cyp1a1-Ren2 rats during control conditions (filled bars) and after intrarenal bolus injection of aliskiren (hatched bars). ***P < 0.001.

Fig. 8.

Urinary ANG II excretion rate in noninduced and hypertensive Cyp1a1-Ren2 rats during control conditions (filled bars) and after intrarenal bolus injection of aliskiren (hatched bars). *P < 0.05.

Fig. 9.

Plasma ANG II concentration in noninduced and hypertensive Cyp1a1-Ren2 rats during control conditions (filled bars) and after intrarenal bolus injection of aliskiren (hatched bars). ***P < 0.001.

Fig. 10.

Urinary protein excretion rate in noninduced and hypertensive Cyp1a1-Ren2 rats during control conditions (filled bars) and after intrarenal bolus injection of aliskiren (hatched bars). **P < 0.01.