Regulation of renal growth factors and clusterin by AT1 receptors during neonatal ureteral obstruction

Abstract

Unilateral ureteral obstruction (UUO) in the neonate impairs growth of the ipsilateral kidney. Since renal renin expression is increased by UUO, we hypothesized that, by activation of AT1 receptors, angiotensin II (ANG II) regulates expression of transforming growth factor-beta 1 (TGF-beta 1) and epidermal growth factor (EGF) in the obstructed kidney. Sprague-Dawley rats underwent left UUO or sham operation within the first 48 h of life and received losartan, 40 mg.kg-1.day-1, or saline. After 14 days, steady-state renal mRNA was determined for renin, TGF-beta 1, EGF, and clusterin. Losartan reduced the DNA content of the intact kidneys but did not further decrease that of the obstructed kidney. Losartan increased renal renin expression and decreased EGF expression by 80%, regardless of UUO. In contrast, losartan reduced TGF-beta 1 expression by 34% in obstructed kidneys but did not affect TGF-beta 1 in intact kidneys. Losartan increased clusterin expression by 60% in obstructed kidneys and seven-fold in intact kidneys. We conclude that activation of the ANG II AT1 receptor is necessary for normal renal growth and that TGF-beta 1 is regulated by AT1 receptors in the obstructed, but not intact, kidneys. Through AT1 receptors, endogenous ANG II stimulates EGF and inhibits clusterin expression.