Lack of cardiac fibrosis in a new model of high prorenin hyperaldosteronism

Abstract

The aim of the present study was to test the hypothesis that elevation of prorenin in plasma is sufficient to induce cardiac fibrosis. Normotensive cyp1a1ren-2 transgenic rats with normal plasma prorenin and aldosterone levels were given 0.125% indole-3-carbinol (I3C) orally for a period of 12 wk. Plasma prorenin and aldosterone levels were determined in 4-wk intervals, and cardiac marker enzymes for hypertrophy, fibrosis, and oxidative stress as well as cardiac pathology were investigated. In I3C-treated cyp1a1 ren-2 transgenic rats, plasma prorenin concentrations were >100-fold elevated (≥7.1 ± 2.6 μg ANG I·ml−1·h−1 vs. ≤0.07 ± 0.1; P < 0.001), whereas active renin levels were suppressed (0.09 ± 0.02 vs. 0.2 ± 0.1; P < 0.05). Aldosterone concentrations were elevated three- to fourfold for a period of >4 wk (574 ± 51 vs. 160 ± 68 pg/ml; P < 0.01). After 12 wk of I3C, rats exhibited moderate cardiac hypertrophy (heart weight/body weight 2.5 ± 0.04 vs. 3.1 ± 0.1 mg/g; P < 0.01). There was a slight increase in mRNA contents of endothelin 1 (1.21 ± 0.08 vs. 0.75 ± 0.007; P < 0.001), NADP oxidase-2 (1.03 ± 0.006 vs. 0.76 ± 0.04; P < 0.001), transforming growth factor-β (0.99 ± 0.06 vs. 0.84 ± 0.04; P < 0.05), collagen type I (1.32 ± 0.32 vs. 0.94 ± 0.18; P < 0.05), and intercellular adhesion molecule-1 (1.12 ± 0.12 vs. 0.84 ± 0.08; P < 0.05). These genes are known to be stimulated by the renin-angiotensin system. There were no histological signs of fibrosis in the heart. We found that prorenin and aldosterone alone are not sufficient to induce considerable cardiac fibrosis in the absence of sodium load.

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

“…ANG II-dependent hypertension is historically associated with cardiac fibrosis and end-organ injury (14), but surprisingly, cardiac fibrosis was not observed following low-dose I3C administration in this transgenic rat model (24). Little information is available regarding the effects of high-dose I3C (0.3% wt/wt) on cardiac fibrosis, which was the dose utilized in the present study.…”

“…In addition to significant renal pathological changes, other groups have reported the development of cardiac hypertrophy in Cyp1a1-Ren2 transgenic rats induced with either low-dose I3C (0.125% wt/wt) (24) or high-dose I3C (0.3% wt/wt) (28). ANG II-dependent hypertension is historically associated with cardiac fibrosis and end-organ injury (14), but surprisingly, cardiac fibrosis was not observed following low-dose I3C administration in this transgenic rat model (24).…”

Cardiac remodeling during and after renin–angiotensin system stimulation in Cyp1a1-Ren2 transgenic rats

“…9 In IHR cardiac fibrosis did not even occur after a three-month I3C activation. 20 Additionally, in Ang II infused rats signs of heart failure were observed already within two weeks of infusion. 21 …”

Molecular changes in the early phase of renin-dependent cardiac hypertrophy in hypertensive cyp1a1ren-2transgenic rats

“…18 Instead, we can relate to previous work because the dose-dependent induction is highly reproducible in this model. [16][17][18] The molecular physiology of cardiac hypertrophy comprises the functional and transcriptional regulation of ion channels, ion exchangers, and Ca 2+ -handling proteins, among other adaptations. This initial adaptive physiological remodelling is thought to be the basis for the later irreversible structural remodelling characteristic for hypertrophy.…”