Aldosterone receptor antagonism alleviates proteinuria, but not malignant hypertension, in Cyp1a1-Ren2 transgenic rats

• Published in: American journal of physiology. Renal physiology 2007-11, Vol.293 (5), p.F1584-F1591
• Main Authors: Ortiz, Rudy M, Graciano, Miguel L, Mullins, John J, Mitchell, Kenneth D
• Format: Article
• Language: English
• Subjects: Adrenal Glands - metabolism; Adrenal Glands - pathology; Aldosterone - metabolism; Aldosterone - urine; Angiotensin II - metabolism; Animals; Animals, Genetically Modified; Blood Pressure; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1A1 - metabolism; Hematocrit; Hormones; Hypertension; Hypertension, Malignant - metabolism; Hypertension, Malignant - pathology; Hypertension, Malignant - physiopathology; Hypertension, Malignant - prevention & control; Kidney - metabolism; Kidney - pathology; Male; Mineralocorticoid Receptor Antagonists - pharmacology; Myocardium - pathology; Nephrology; Organ Size; Proteins; Proteinuria - metabolism; Proteinuria - physiopathology; Rats; Renin - genetics; Renin - metabolism; Rodents; Sodium - urine; Spironolactone - pharmacology
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00124.2007

The contribution of elevated aldosterone to the pathogenesis of malignant, ANG II-dependent hypertension remains uncertain. Therefore, we examined whether chronic mineralocorticoid receptor blockade attenuates the development of malignant hypertension in transgenic rats (TGRs) with inducible expression of the Ren2 gene [TGR(Cyp1a1Ren2)]. Systolic blood pressure (SBP) was measured by radiotelemetry in male TGRs in three groups: 1) control (n = 9), 2) hypertensives (HT; n = 8), and 3) hypertensives + spironolactone (11 mg.kg(-1).day(-1) sc; HTS; n = 8). Malignant hypertension was induced with dietary indole-3-carbinol (0.3%) for 10 days. Metabolic measurements were taken at the beginning of the study and at days 2 and 9. HT exhibited elevated SBP (125 +/- 3 vs. 187 +/- 5 mmHg), plasma renin activity (5 +/- 1 vs. 29 +/- 10 ng ANG I.ml(-1).h(-1)), plasma ANG II (175 +/- 39 vs. 611 +/- 74 fmol/ml), and plasma aldosterone (0.31 +/- 0.04 vs. 5.42 +/- 1.02 nmol/l). Urinary aldosterone excretion increased 5.5-fold by day 2 and an additional 90% by day 9. HT was associated with a 1.8-fold increase in proteinuria by day 9 that was alleviated by treatment with spironolactone (25 +/- 5 vs. 13 +/- 3 mg/day), suggesting that aldosterone contributes to the renal damage observed in malignant hypertension. Urinary Na+ excretion was decreased 76% on day 2, despite a sixfold increase in urinary aldosterone excretion. Decrease in urinary Na+ excretion on day 2 in HT suggests that Na+ reabsorption was increased in response to the increase in aldosterone; however, the lack of a change in SBP between HT and HTS suggests that mechanisms independent of aldosterone stimulation make a greater contribution to the maintenance of elevated arterial pressure in malignant hypertension in Cyp1a1-Ren2 transgenic rats.