AT1 antagonist modulates activin-like kinase 5 and TGF-beta receptor II in the developing kidney.
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.
Yim
Hyung Eun
HE
Department of Pediatrics, College of Medicine, Korea University, 152-703 Seoul, South Korea.
Kim
Mee Kyung
MK
Bae
In Sun
IS
Kim
Ji Hae
JH
Choi
Byung Min
BM
Yoo
Kee Hwan
KH
Hong
Young Sook
YS
Lee
Joo Won
JW
D000199:Actins / Q000235:genetics / Q000378:metabolism; D030201:Activin Receptors, Type I / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000502:physiology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D007668:Kidney / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology*; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000502:physiology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
D000199:Actins; D030201:Activin Receptors, Type I; D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D019808:Losartan; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C498862:Acta2 protein, rat; C000625843:Tgfbr1 protein, rat