Angiotensin-converting enzyme inhibition decreases growth factor expression in the neonatal rat kidney

Abstract

The renin-angiotensin system plays an important role in renal growth and development: exposure of the fetus or neonate to angiotensin-converting enzyme (ACE) inhibitors increases mortality and results in growth retardation and abnormal renal development. This study was designed to investigate the effects of ACE inhibition in the neonatal rat on the expression of genes known to modulate renal cellular proliferation, cell interactions, and extracellular matrix. Newborn rat pups were treated with enalapril (30 mg/kg/d) or vehicle for 14 d, and kidneys were removed for Northern analysis of mRNA for transforming growth factor-beta1 (TGF-beta1), prepro epidermal growth factor (EGF), clusterin, and renin. Distribution of TGF-beta1, EGF, and clusterin was also determined by immunohistochemistry. Enalapril treatment resulted in 40% mortality by d 14, reduced body and kidney weight, decreased glomerular area, and caused tubular dilatation (p < 0.05 versus vehicle group). Enalapril decreased renal TGF-beta1 and EGF mRNA expression, and increased renal clusterin and renin expression (p < 0.05). Renal tubular immunoreactive EGF was decreased, and clusterin was increased by enalapril treatment. These results indicate that ACE inhibition in the developing kidney reduces the renal expression of critical growth factors, which may account for renal growth impairment. Clusterin expression may increase either due to blockade of tonic angiotensin-mediated inhibition, or as an adaptive response to renal ischemia.