An intact renin-angiotensin system is essential for normal renal development

Abstract

The renin-angiotensin system (RAS) is important in the regulation of extracellular fluid volume and systemic blood pressure. In a previous study we accidentally found that pharmacological blockade of the RAS in neonatal rats with immature kidneys produced persistent renal morphological abnormalities. This observation suggested that the RAS, in addition to exerting its traditional functions in the control of circulatory homeostasis, may play a role in normal renal development. The aims of the present studies were to perform a detailed investigation of the consequences of neonatal inhibition of the RAS on long-term renal morphology and function in the rat. Moreover, we wanted to elucidate the specific postnatal time interval during which the rat kidney is vulnerable to an inhibition of the RAS, and whether our observations could be reproduced in a non-rodent kidney. Neonatal rats and piglets received daily intraperitoneal injections of the angiotensin-converting enzyme (ACE) inhibitor enalapril during the first 3 weeks after birth. Renal function was analyzed in adult rats using a combination of metabolic balance studies in conscious animals, and renal clearance experiments under anesthesia. Kidney histology was assessed with light microscopy using semiquantitative and stereological methods. ACE inhibition attenuated somatic growth in the neonate and produced persistent renal histopathological alterations characterized by papillary atrophy, interstitial fibrosis and chronic inflammation, tubular atrophy and dilatation, and wall thickening of interlobular arteries, in both rats and pigs. Functionally, adult rats subjected to neonatal ACE inhibition showed: an approximate 15 % reduction in glomerular filtration rate and effective renal plasma flow; an impaired urinary concentrating ability of renal origin; sodium retention during dietary sodium loading; and a modest and transient potassium wastage during dietary potassium restriction. In spite of the renal histological lesions, neonatally enalapril-treated rats displayed an intact sodium conservation during dietary sodium restriction and a preserved urinary acidification and net acid excretion. The renal lesions induced by enalapril did not seem to be the result of renal ischemia secondary to an arterial pressure reduction, as a blood pressure lowering control drug (nifedipine) did not produce any renal abnormalities. Postnatally, the rat kidney was vulnerable to ACE inhibition during the first 16 days specifically. The only renal abnormality associated with enalapril treatment after 14 days of age, i.e. after nephrogenesis had ceased, was a reduction in the volume fraction of tubular epithelium in the inner stripe of the outer medulla, which is the kidney zone last to mature, suggesting that angiotensin II may promote tubulogenesis at a stage in renal development when nephrogenesis has been completed. Taken together, the present studies demonstrate an essential role for the RAS in normal renal development. These findings underline that drugs which interrupt the RAS should be strictly avoided by pregnant women, and possibly also in newborns with immature kidneys. Moreover, results in the present studies may add to our understanding and care of renal diseases associated with a suppressed RAS during development.