Pediatric Nephrology

, Volume 21, Issue 10, pp 1377–1388 | Cite as

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

  • Hyung Eun Yim
  • Mee Kyung Kim
  • In Sun Bae
  • Ji Hae Kim
  • Byung Min Choi
  • Kee Hwan YooEmail author
  • Young Sook Hong
  • Joo Won Lee
Original Article


Previous studies by our group have demonstrated that angiotensin-converting enzyme (ACE) inhibition in the developing kidney modulates transforming growth factor-β 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-β1 (TGF-β1), TGF-β receptor I [TβRI, activin-like kinase (ALK)-1, ALK-5], TGF-β receptor II (TβRII), and α-smooth muscle actin (α-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-β1, ALK-1, ALK-5, TβRII, and α-SMA. Renal ALK-5 and TβRII protein expressions in the losartan-treated group were found to be significantly increased (P<0.05), whereas TGF-β1, ALK-1, and α-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 TβRII.


Angiotensin II type 1 receptor Transforming growth factor-β1 TGF-β receptors 


  1. 1.
    Kriz W, LeHir M (2005) Pathways to nephron loss starting from glomerular diseases—insights from animal models. Kidney Int 67:404–419CrossRefGoogle Scholar
  2. 2.
    Schnaper HW, Hayashida T, Hubchak SC, Poncelet AC (2003) TGF-beta signal transduction and mesangial cell fibrogenesis. Am J Physiol Renal Physiol 284:F243–F252CrossRefGoogle Scholar
  3. 3.
    Basile DP, Hammerman MR (1998) TGF-beta in renal development and renal growth. Miner Electrolyte Metab 24:144–148CrossRefGoogle Scholar
  4. 4.
    de Caestecker M (2004) The transforming growth factor-beta superfamily of receptors. Cytokine Growth Factor Rev 15:1–11CrossRefGoogle Scholar
  5. 5.
    Abbate M, Zoja C, Rottoli D, Corna D, Tomasoni S, Remuzzi G (2002) Proximal tubular cells promote fibrogenesis by TGF-beta1-mediated induction of peritubular myofibroblasts. Kidney Int 61:2066–2077CrossRefGoogle Scholar
  6. 6.
    Carey AV, Carey RM, Gomez RA (1992) Expression of alpha-smooth muscle actin in the developing kidney vasculature. Hypertension 19(Suppl 2):II168–II175PubMedGoogle Scholar
  7. 7.
    Gonlusen G, Ergin M, Paydas S, Tunali N (2001) The expression of cytoskeletal proteins (alpha-SMA, vimentin, desmin) in kidney tissue: a comparison of fetal, normal kidneys, and glomerulonephritis. Int Urol Nephrol 33:299–305CrossRefGoogle Scholar
  8. 8.
    Fan JM, Ng YY, Hill PA, Nikolic Paterson DJ, Mu W, Atkins RC, Lan HY (1999) Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiation in vitro. Kidney Int 56:1455–1467CrossRefGoogle Scholar
  9. 9.
    Chen Y, Lasaitiene D, Gabrielesson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004) Neonatal losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. J Am Soc Nephrol 15:1232–1243CrossRefGoogle Scholar
  10. 10.
    Choi JH, Yoo KH, Cheon HW, Kim KB, Hong YS, Lee JW, Kim SK, Kim CH (2002) Angiotensin converting enzyme inhibition decreases cell turnover in the neonatal rat heart. Pediatr Res 52:325–332CrossRefGoogle Scholar
  11. 11.
    Yoo KH, Wolstenholme JT, Thornhill BA, Chevalier RL (1998) Tissue-specific regulation of growth factors and clusterin by angiotensin II. Am J Hypertens 11:715–722CrossRefGoogle Scholar
  12. 12.
    Ruiz-Ortega M, Ruperez M, Esteban V, Rodriguez-Vita J, Sanchez-Lopez E, Carvajal G, Egido J (2006) Angiotensin II: a key factor in the inflammatory and fibrotic response in kidney diseases. Nephrol Dial Transplant 21:16–20CrossRefGoogle Scholar
  13. 13.
    Tufro-McReddie A, Romani LM, Harris JM, Ferder L, Gomez RA (1995) Angiotensin II regulates nephrogenesis and renal vascular development. Am J Physiol 269:F110–F115CrossRefGoogle Scholar
  14. 14.
    Choi BM, Yoo KH, Bae IS, Oh MH, Hong YS, Lee JW, Kim SK (2005) Angiotensin converting enzyme inhibition modulates mitogen-activated protein kinase family expressions in the neonatal rat kidney. Pediatr Res 57:115–123CrossRefGoogle Scholar
  15. 15.
    Nagamatsu T, Hayashi K, Oka T, Suzuki Y (1999) Angiotensin II type I receptor antagonist suppresses proteinuria and glomerular lesions in experimental nephritis. Eur J Pharmacol 374:93–101CrossRefGoogle Scholar
  16. 16.
    Suzuki Y, Lopez-Franco O, Gomez-Garre D, Tejera N, Gomez-Guerrero C, Sugaya T, Bernal R, Blanco J, Ortega L, Egido J (2001) Renal tubulointerstitial damage caused by persistent proteinuria is attenuated in AT1-deficient mice: role of endothelin-1. Am J Pathol 159:1895–1904CrossRefGoogle Scholar
  17. 17.
    Kelly DJ, Skinner SL, Gilbert RE, Cox AJ, Cooper ME, Wilkinson-Berka JL (2000) Effects of endothelin or angiotensin II receptor blockade on diabetes in the transgenic (mRen-2)27 rat. Kidney Int 57:1882–1894CrossRefGoogle Scholar
  18. 18.
    Kang NS, Yim HE, Bae IS, Choi JH, Choi BM, Yoo KH, Hong YS, Lee JW, Kim SK (2003) ACE inhibition modulates transforming growth factor-beta receptors in the young rat. Pediatr Nephrol 18:865–871CrossRefGoogle Scholar
  19. 19.
    Tso JY, Sun XH, Kao TH, Reece KS, Wu R (1985) Isolation and characterization of rat and human glyceraldehyde-3-phosphate dehydrogenase cDNAs: genomic complexity and molecular evolution of the gene. Nucleic Acids Res 13:2485–2502CrossRefGoogle Scholar
  20. 20.
    Bassing CH, Yingling JM, Howe DJ, Wang T, He WW, Gustafson ML, Shah P, Donahoe PK, Wang XF (1994) A transforming growth factor beta type I receptor that signals to activate gene expression. Science 263:87–89CrossRefGoogle Scholar
  21. 21.
    Choi ME, Kim EG, Huang Q, Ballermann BJ (1993) Rat mesangial cell hypertrophy in response to transforming growth factor-beta 1. Kidney Int 44:948–958CrossRefGoogle Scholar
  22. 22.
    Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254CrossRefGoogle Scholar
  23. 23.
    Yoo KH, Cheon HW, Choi BM, Hong YS, Lee JW, Kim SK (1998) Angiotensin converting enzyme inhibition increases apoptosis and bcl-2 expression in the neonatal rat kidney. J Am Soc Nephrol 9:A2613Google Scholar
  24. 24.
    Yoo KH, Choi JH, Kim MK, Hong YS, Lee JW, Kim SK (2000) Angiotensin-converting enzyme inhibition modulates platelet derived growth factors, receptors, and alpha smooth muscle actin expression in the neonatal kidney. J Am Soc Nephrol 11:A385Google Scholar
  25. 25.
    Shin GT, Kim SJ, Ma KA, Kim HS, Kim D (2000) ACE inhibitors attenuate expression of renal transforming growth factor-beta1 in humans. Am J Kidney Dis 36:894–902CrossRefGoogle Scholar
  26. 26.
    Fukuda N, Hu WY, Kubo A, Kishioka H, Satoh C, Soma M, Izumi Y, Kanmatsuse K (2000) Angiotensin II upregulates transforming growth factor-beta type I receptor on rat vascular smooth muscle cells. Am J Hypertens 13:191–198CrossRefGoogle Scholar
  27. 27.
    Sun BK, Li C, Lim SW, Choi BS, Lee SH, Kim IS, Kim YS, Bang BK, Yang CW (2005) Blockade of angiotensin II with losartan attenuates transforming growth factor-beta1 inducible gene-h3 (betaig-h3) expression in a model of chronic cyclosporine nephrotoxicity. Nephron Exp Nephrol 99:e9–e16CrossRefGoogle Scholar
  28. 28.
    Wolf G, Ziyadeh FN, Stahl RA (1999) Angiotensin II stimulates expression of transforming growth factor beta receptor type II in cultured mouse proximal tubular cells. J Mol Med 77:556–564CrossRefGoogle Scholar
  29. 29.
    Hill C, Logan A, Smith C, Gronbaek H, Flyvbjerg A (2001) Angiotensin converting enzyme inhibitor suppresses glomerular transforming growth factor beta receptor expression in experimental diabetes in rats. Diabetologia 44:495–500CrossRefGoogle Scholar
  30. 30.
    Yoo KH, Wolstenholme JT, Chevalier RL (1997) Angiotensin-converting enzyme inhibition decreases growth factor expression in the neonatal rat kidney. Pediatr Res 42:588–592CrossRefGoogle Scholar
  31. 31.
    Yoo KH, Norwood, El-Daha SS, Yosipiv, Chevalier RL (1997) Regulation of angiotensin II AT1 and AT2 receptors in neonatal ureteral obstruction. Am J Physiol 273:R503–R509PubMedGoogle Scholar
  32. 32.
    Siragy HM (2000) AT1 and AT2 receptors in the kidney: role in disease and treatment. Am J Kidney Dis 36:S4–S9CrossRefGoogle Scholar
  33. 33.
    Jaspard E, Wei L, Alhenc-Gelas F (1993) Differences in the properties and enzymatic specificities of the two active sites of angiotensin I-converting enzyme (kininase II). Studies with bradykinin and other natural peptides. J Biol Chem 268:9496–9503PubMedGoogle Scholar
  34. 34.
    Yosipiv IV, Dipp S, El-Dahr SS (1997) Role of bradykinin B2 receptors in neonatal kidney growth. J Am Soc Nephrol 8:920–928PubMedGoogle Scholar
  35. 35.
    Cellier E, Mage M, Duchene J, Pecher C, Couture R, Bascands JL, Girolami JP (2003) Bradykinin reduces growth factor-induced glomerular ERK1/2 phosphorylation. Am J Physiol Renal Physiol 284:F282–F292CrossRefGoogle Scholar
  36. 36.
    Mariano JM, Montuenga LM, Prentice MA, Cuttitta F, Jakowlew SB (1998) Concurrent and distinct transcription and translation of transforming growth factor-beta type I and type II receptors in rodent embryogenesis. Int J Dev Biol 42:1125–1136PubMedGoogle Scholar
  37. 37.
    Choi ME, Liu A, Ballermann BJ (1997) Differential expression of transforming growth factor-beta receptors in rat kidney development. Am J Physiol 273:F386–F395PubMedGoogle Scholar

Copyright information

© IPNA 2006

Authors and Affiliations

  • Hyung Eun Yim
    • 1
  • Mee Kyung Kim
    • 1
  • In Sun Bae
    • 1
  • Ji Hae Kim
    • 1
  • Byung Min Choi
    • 1
  • Kee Hwan Yoo
    • 1
    • 2
    Email author
  • Young Sook Hong
    • 1
  • Joo Won Lee
    • 1
  1. 1.Department of PediatricsCollege of Medicine, Korea UniversitySeoulSouth Korea
  2. 2.Department of PediatricsGuro Hospital, Korea University Medical CenterSeoulSouth Korea

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