Angiotensin and Bradykinin Peptides in the TGR(mRen-2)27 Rat

Abstract

The transgenic TGR(mRen-2)27 rat, in which the Ren-2 mouse renin gene is transfected into the genome of the Sprague-Dawley rat, develops severe hypertension at a young age that responds to inhibitors of angiotensin-converting enzyme and to antagonists of the type 1 angiotensin II (Ang II) receptor. Despite this evidence that the hypertension is Ang II dependent, TGR(mRen-2)27 rats have suppressed renal renin and renin mRNA content, and there is controversy concerning the plasma levels of renin and Ang II in these rats. We investigated the effect of the transgene on circulating and tissue levels of angiotensin and bradykinin peptides in 6-week-old male homozygous TGR(mRen-2)27 rats. Systolic blood pressure of TGR(mRen-2)27 rats was 212 +/- 4 mm Hg (mean +/- SEM, n = 25) compared with 108 +/- 2 mm Hg (n = 29) for age- and sex-matched Sprague-Dawley rats. Compared with control rats, TGR(mRen-2)27 rats had increased plasma levels of active renin (4.5-fold), prorenin (300-fold), and Ang II (fourfold) as well as tissue levels of Ang II (twofold to fourfold in kidney, adrenal, heart, aorta, brown adipose tissue, and lung and 18-fold in brain). Plasma angiotensinogen levels were reduced to 73% of control, and plasma aldosterone levels were increased fourfold. Plasma angiotensin-converting enzyme was reduced to 64% of control. Compared with control rats, TGR(mRen-2)27 rats had increased bradykinin levels in brown adipose tissue (1.9-fold) and lung (1.6-fold).(ABSTRACT TRUNCATED AT 250 WORDS)

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

“…The lower plasma active renin level in diabetic Ren-2 rats, in comparison with non-diabetic Ren-2 rats, was in agreement with our report of lower plasma angiotensin II and angiotensin I levels in diabetic Ren-2 rats, although we did not find a reduction in plasma active renin levels in our previous study [47]. The Ren-2 rat has elevated levels of mouse renin and angiotensin peptides in plasma and tissues [48] that suppress renal expression of rat renin. Inhibition of angiotensin II formation, such as by ACE inhibition, reverses the suppression of renal expression of rat renin [49], thereby accounting for the increase in plasma active renin levels in sham and diabetic Ren-2 rats administered lisinopril.…”

Renin overexpression leads to increased titin-based stiffness contributing to diastolic dysfunction in hypertensive mRen2 rats

“…LV hypertrophy is another prominent feature of mRen2 rats (34), which was confirmed in our experiments. In this respect, there are studies suggesting functional expression of the transgene in the myocardium, providing a direct link between the genotype and phenotype (9,28), although one may argue that severe HTN (cardiac overload) can lead to cardiac hypertrophy independently of the myocardial RAAS.…”

Hypertension in the (mRen-2)27 Rat Is Not Explained by Enhanced Kinetics of Transgenic Ren-2 Renin

“…That plasma Ang II is not suppressed is now apparent, with resting levels increased up to 4-fold in both young 9 and adult 10 Ren-2 rats. One would expect a similar elevation of plasma active renin, but this depends on the pH at which the activity is estimated, 11,12 because mouse and rat renins have different pH optima when acting on rat aogen (pH 8.5 and 6.5, respectively).…”

“…11,12 By comparison with other high-renin models that cause malignant hypertension, the Ϸ4-fold increase in plasma renin and Ang II would not seem a sufficient explanation for the degree of hypertension that develops rapidly in the mature animal. However, tissue levels of Ang II are also increased, by as much as 20-fold in the brain and 3-fold in the kidney, 9 and would be expected to have accelerating effects on the hypertensive process.…”