AT1 antagonist modulates activin-like kinase 5 and TGF-beta receptor II in the developing kidney

Abstract

Previous studies by our group have demonstrated that angiotensin-converting enzyme (ACE) inhibition in the developing kidney modulates transforming growth factor-beta receptors. Blocking of angiotensin II (ANG II) mainly through angiotensin II type 1 receptor (AT1) has been implicated in mediating this ACE inhibition. The present study was designed to investigate the effects of an AT1 antagonist, losartan, on transforming growth factor-beta1 (TGF-beta1), TGF-beta receptor I [TbetaRI, activin-like kinase (ALK)-1, ALK-5], TGF-beta receptor II (TbetaRII), and alpha-smooth muscle actin (alpha-SMA) expression in the developing kidney. Newborn rat pups were treated with losartan (30 mg/kg per day) or normal saline for 7 days. Kidneys were removed for immunohistochemistry, reverse transcription polymerase chain reaction (PCR), and Western blotting of TGF-beta1, ALK-1, ALK-5, TbetaRII, and alpha-SMA. Renal ALK-5 and TbetaRII protein expressions in the losartan-treated group were found to be significantly increased (P<0.05), whereas TGF-beta1, ALK-1, and alpha-SMA protein expressions were not changed by losartan treatment. The losartan-treated group also showed significantly increased mean tubular diameter and interstitial area of the kidney (P<0.05). These results suggest that AT1 inhibition in the developing kidney impairs renal growth and development and modulates the expression of ALK-5 and TbetaRII.