Postnatal Time Frame for Renal Vulnerability to Enalapril in Rats

Angiotensin-converting enzyme inhibition or angio- tensin II type 1 receptor blockade in neonatal, but not in weaned, rats induces irreversible renal histologic abnormalities and an impaired urinary concentrating ability. The aim of the present study was to define the postnatal time frame when the rat kidney is vulnerable to an interruption of the renin-angio- tensin system. Male Wistar rats received daily injections of enalapril (10 mg/kg, intraperitoneally) during different age intervals within 3 to 24 d of age. Fluid handling and urinary concentrating ability, renal function under pentobarbital anes- thesia, and kidney histology using stereologic techniques were evaluated in adult rats. Enalapril treatment within 3 to 13 d after birth induced abnormalities in renal function and mor- phology long-term, whereas treatment initiated at 14 d of age did not. The main histologic alterations were papillary atrophy, and a reduction in the volume of tubular epithelial cells in association with an increase in the proportion of interstitium, throughout the cortex and outer medulla. Functionally, the predominant defect was an impairment in urinary concentrat- ing ability, which correlated with the degree of papillary atro- phy. In conclusion, the vulnerable age interval for the induction of irreversible renal abnormalities by enalapril was the first 13 d after birth in the rat. This postnatal time span coincides with the completion of nephrogenesis and a period of marked tubular growth and differentiation, suggesting a pivotal role for angiotensin II in these processes. All components of the renin-angiotensin system (RAS) are expressed in the immature kidney and are developmentally regulated in a tissue-specific manner, with increased gene expression and elevated renal angiotensin II (AngII) content occurring perinatally compared with the adult (1,2). Although the physiologic role of the RAS in the developing kidney remains to be elucidated, the spatio-temporal pattern of the expression of AngII receptors (3-5), together with in vitro evidence showing trophic and proliferative effects of AngII on different renal cell types (6), has suggested that AngII may be involved in the regulation of renal growth and differentiation. In support of this notion, angiotensin-converting enzyme (ACE) inhibition or AngII type 1 (AT1) receptor antagonism has been shown to inhibit renal growth (7) and induce renal histopathologic abnormalities (7-9) in the neonatal rat. Con- firmation of an essential role for the RAS in renal development has recently been provided by gene-targeting studies, in which mice deficient in ACE (10,11) or angiotensinogen (12,13) developed alterations in renal histology similar to those ob-