Renin-angiotensin system in neonatal rats: Induction of a renal abnormality in response to ACE inhibition or angiotensin II antagonism

Abstract

In experiments designed to analyze cardiovascular structure in response to antihypertensive therapy with an ACE inhibitor, we decided to start very early in life with the aim to prevent blood pressure increases and the development of vascular structural changes. In these treated groups of rats we unexpectedly observed that after they were weaned, their water consumption and urine volume, respectively, increased substantially. The present study was designed to determine if inhibition of the renin-angiotensin system produced similar effects in different strains of rats, and focused on characterizing the abnormal fluid balance occurring as a consequence to neonatal treatment with ACE inhibitors or angiotensin II blockers. Three-day-old Wistar Kyoto (WKY), Wistar (WR) and spontaneously hypertensive rats (SHR) were given either saline, enalapril, captopril, losartan and the AT2 blocker, PD123319, in the same amount of volume for 20 days. Treatment was stopped and rats were examined with regard to renal morphology at 4, 14 and 30 weeks of age. In addition, water consumption, urine volume, urine electrolytes and osmolality were analyzed at 14 weeks of age, that is, 10 weeks off treatment. Early treatment with the ACE inhibitors, enalapril and captopril, and the AT1 blocker, losartan, but not the AT2 blocker, PD 123319, in the SHR and in the normotensive strains WKY and WR produced persistent, irreversible histopathological renal abnormalities in adult life, long after the rats had been taken off treatment. These abnormalities consisted of mainly cortical tubulointerstitial inflammation, various degrees of papillary atrophy and pelvic dilation.(ABSTRACT TRUNCATED AT 250 WORDS)

The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice.

“…It has previously been reported that mice completely lacking ACE develop renal lesions that involve blunting of the renal papilla and associated dilatation of the renal calyces (17). These lesions are almost certainly due to lack of angiotensin II production since they also occur in mice that lack angiotensinogen and in rats treated neonatally with AT 1 receptor antagonists (23,24,26). It is not clear whether the renal abnormalities are due directly to a requirement for angiotensin II in normal renal development, or if they are secondary to the low blood pressure or increased urine flow present in these animals.…”

Roles of mitogen-activated protein kinases and angiotensin II in renal development

“…Neonatal rats treated with an angiotensin-converting enzyme inhibitor presented persistent and irreversible histopathological renal abnormalities in adult life (37). These abnormalities mainly consisted of cortical tubulointerstitial inflammation, various degrees of papillary atrophy and pelvic dilation.…”

Prenatal Programming of Hypertension

“…The role of the RAS in altered renal development has received considerable attention. Angiotensin II is known to be important in normal renal development (109,110), and variations in dietary protein can alter the RAS (111). In the rat low-protein model, we have shown that renal tissue renin protein and mRNA, AT1R protein and mRNA, and angiotensin II levels are reduced in the newborn and young offspring compared with controls (16,19,97).…”