1. Hypertension plays a critical role in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD), but it has also been postulated that antihypertensive drugs that block the renin-angiotensin system (RAS) show class-specific renoprotective actions beyond their blood pressure (BP)-lowering effects. 2. Because this notion has recently been questioned, in the present study we compared the effects of a RAS-dependent antihypertensive therapy (a combination of trandolapril, an angiotensin-converting enzyme inhibitor (ACEI) and losartan, an angiotensin-II (AngII) receptor subtype 1A receptor antagonist) with a 'RAS-independent' antihypertensive therapy (a combination of labetalol, an alfa- and beta-adrenoreceptor antagonist with the diuretics, hydrochlorothiazide and furosemide) on the progression of CKD after 5/6 renal ablation (5/6 NX) in Ren-2 renin transgenic rats (TGR), a model of AngII-dependent hypertension. Normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats after 5/6 NX served as controls. 3. RAS-dependent and -independent antihypertensive therapies normalized BP and survival rate, and prevented the development of cardiac hypertrophy and glomerulosclerosis to the same degree in 5/6 NX HanSD rats and in 5/6 NX TGR. The present findings show that renoprotection, at least in rats after 5/6 NX, is predominantly BP-dependent. When equal lowering of BP was achieved, leading to normotension, cardio- and renoprotective effects were equivalent irrespective of the type of antihypertensive therapy. 4. These findings should be taken into consideration in attempts to develop new therapeutic approaches and strategies aimed to prevent the progression of CKD and to lower the incidence of ESRD.

Our findings indicate that hypertension in Cyp1a1-Ren-2 rats is a clearly angiotensin II-dependent model of hypertension with elevated circulating and tissue angiotensin II concentrations, and that antihypertensive treatment with AT1 receptor blockade is superior to conventional triple therapy in effective protection against hypertension-induced end-organ damage in this rat model.

Objective The present study was performed to examine in two-kidney, one clip (2K1C) Goldblatt hypertensive mice, first, the relative contribution of angiotensin II (ANG II) receptor subtypes 1A (AT1A) and 1B (AT1B); second, the role of ANG II type 2 (AT2) receptors in the development of hypertension in wild-type (AT1A+/+) and AT1A receptor knockout (AT1A−/−) mice and third, the role of increased nitric oxide synthase (NOS) activity in counteracting the hypertensinogenic action of ANG II in this model. Methods AT1A+/+ and AT1A−/− mice underwent clipping of one renal artery and were infused with either saline vehicle or with the selective AT2 receptor agonist CGP-42112A (CGP). Blood pressure (BP) was monitored by radiotelemetry. BP responses to the NOS inhibitor nitro-L-arginine-methyl-ester (L-NAME) were evaluated. Results AT1A+/+ mice responded to clipping by a rise in BP which was not modified by CGP infusion. Clip placement caused a slight increase in BP in AT1A−/− mice which remained significantly lower than in AT1A+/+ mice. Acute NOS inhibition caused greater increases in BP in 2K1C/AT1A+/+ than in AT1A+/+ mice. Conclusions The present data support the critical role AT1A receptors in the development of 2K1C hypertension, whereas AT1B receptors play only a minor role in BP regulation in this model of ANG II-dependent hypertension. Activation of AT2 receptors does not play an antagonistic role in the AT1 receptor-mediated hypertensinogenic actions of ANG II in this model. Finally, enhanced NOS activity plays a protective role by counteracting the vasoconstrictor influences of ANG II in 2K1C hypertensive mice.

Our results demonstrate that after induction of the renin gene in Cyp1a1-Ren-2 transgenic rats inappropriate increases in plasma and kidney ANG II levels in response to very high dietary salt intake are responsible for the development of severe hypertension in this model of inducible renin transgenic rats.

The present data support the notion that Ang-(1-7) serves as an important endogenous vasodilator and natriuretic agent and its deficiency might contribute to the acceleration of 2K1C Goldblatt hypertension.