Interruption of the renin-angiotensin system during renal development. Acute and long-term consequences

An intact renin-angiotensin system (RAS) during nephrogenesis is pivotal for normal renal development and function. Neonatal inhibition of the angiotensin-converting enzyme (ACE) or the angiotensin II type-1 receptor (AT1), but not the AT2-receptor, results in irreversible and progressive abnormalities of the renal morphology, mainly consisting of a severe papillary atrophy. Functionally, these alterations result in an impaired urinary concentrating ability of renal origin. The mechanisms whereby RAS plays an essential role in renal development are still unknown. The general aims of the present study were to elucidate the consequences of neonatal ACE inhibition for long-term blood pressure regulation and renal handling of sodium and water, particularly with regard to the prevailing papillary atrophy. An additional aim was to evaluate the consequences of ongoing neonatal ACE inhibition on renal haemodynamics and growth signalling, by means of studying the interaction between RAS and the insulin-like growth factor-1 (IGF-I). Neonatal rats were treated with daily intraperitoneal injections of the ACE inhibitor enalapril, during the first three weeks of life. In a separate group of rats, both enalapril and IGF-I were administered. The consequences of the prevailing papillary atrophy on renal interstitial hydrostatic pressure (RIHP), urinary sodium excretion and renal function were investigated in anaesthetised rats. Metabolic balance studies were performed in conscious adult rats during standard dietary procedures, thirst provocation and manipulations of sodium intake during simultaneous 24-hour telemetric blood pressure recordings. Renal histology was investigated by means of detailed morphometry. The acute intrarenal responses to ACE inhibition were investigated in the anaesthetised 4-5 day-old piglet. Neonatal ACE inhibition resulted in reduced RIHP that correlated to the degree of papillary atrophy. The relationship between the renal perfusion pressure and RIHP was maintained, thereby demonstrating an adapted pressure-natriuresis curve in association with an increased baseline RAS activity. Acute ACE inhibition in the immature kidney did neither affect local renal blood flow nor medullary oxygen tension, whereas the medullary IGF-I gene expression was suppressed during ongoing treatment. Interestingly, combined enalapril and IGF-I treatment attenuated the morphological and functional abnormalities produced by sole neonatal ACE inhibition. In conclusion, the adequate sodium balance and blood pressure regulation in adult rats, subjected to neonatal ACE inhibition, are associated with an increased baseline activity of the RAS. Moreover, neonatal RAS inhibition does not cause medullary hypoxia during ongoing treatment but interrupts the interaction between the RAS and IGF-I. It is intriguing to speculate that the role of the RAS in renal growth and differentiation is pivotal, and at least partially mediated through the IGF-I system