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ACE and AT1 receptor gene polymorphisms and renal scarring in urinary bladder dysfunction

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Abstract

The objective of this study was to investigate whether DNA polymorphisms of the renin-angiotensin system (RAS) genes were associated with renal scar formation in pediatric patients with bladder dysfunction (BD). Although these children are born healthy, due to persistence of immature voiding habits and evolution of BD, some develop progressive renal damage. It has been suggested that the DD genotype of the angiotensin I-converting enzyme (ACE) gene might be an adverse renal prognostic factor. The insertion/deletion (I/D) polymorphism of the ACE gene and the A1166C polymorphism of the angiotensin II type 1 receptor (ATR1) gene were identified by polymerase chain reaction amplification in 42 children with BD (aged 5–14 years) and 198 healthy adult controls. Twelve children had urgency syndrome and 30 had dysfunctional voiding. Renal scarring was found in 16 patients, while 26 patients had normal kidneys on dimercaptosuccinic acid scan. In children with renal lesions there was significant over-representation of the DD genotype compared with either controls or patients without renal damage (P<0.05). On multivariate analysis, the DD genotype was the only factor that had a significant impact on renal scar formation, introducing a 2.51-fold risk (odds ratio 2.51, 95% confidence interval 1.04–6.04, P=0.04). The A1166C gene polymorphism was not significantly associated with the development of parenchymal damage in children with BD. Our findings introduce ACE I/D gene polymorphism as an independent risk factor for parenchymal destruction in pediatric patients with BD.

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References

  1. Klahr S, Schreiner G, Ichikawa I (1988) The progression of renal disease. N Engl J Med 318:1657–1666

    CAS  PubMed  Google Scholar 

  2. Egido J (1996) Vasoactive hormones and renal sclerosis. Kidney Int 49:578–597

    CAS  PubMed  Google Scholar 

  3. Wolf G, Neilson EG (1993) Angiotensin II as a renal growth factor. J Am Soc Nephrol 3:1531–1540

    CAS  PubMed  Google Scholar 

  4. Ruiz-Ortega M, Lorenzo O, Egido J (1998) Angiotensin II up-regulates genes involved in kidney damage in mesangial cells and renal interstitial fibroblasts. Kidney Int 54 [Suppl 68]:S41–S45

    Google Scholar 

  5. Navar LG, Imig JD, Zou L, Vang C-T (1997) Intrarenal production of angiotensin II. Semin Nephrol 17:412–422

    CAS  Google Scholar 

  6. Ruiz-Ortega M, Gonzalez S, Seron D, Condom E, Bustos C, Largo R, Gonzalez E, Egido J (1995) ACE inhibition reduces proteinuria, glomerular lesions and extracellular matrix production in normotensive rat model of immune complex nephritis. Kidney Int 48:1778–1791

    CAS  PubMed  Google Scholar 

  7. MacKenzie HS, Ziai F, Omer SA, Nadim MK, Taal MW (1999) Angiotensin receptor blockers in chronic renal disease: the promise of a bright clinical future. J Am Soc Nephrol 10 [Suppl 12]:S283–S286

    Google Scholar 

  8. Yoshida H, Kon V, Ichikawa I (1996) Polymorphisms of the renin-angiotensin system genes in progressive renal diseases. Kidney Int 50:732–744

    PubMed  Google Scholar 

  9. Nonoguchi H, Kiyama S, Inoue H, Nakayama Y, Inoue T, Kohda Y, Machida K, Tajima A, Kitamura K, Miyoshi T, Shimada H, Shimada H, Tajiri M, Honda Y, Tanaka M, Tomita K (2003) Angiotensin-converting enzyme inhibitor withdrawal and ACE gene polymorphism. Clin Nephrol 60:225–232

    CAS  PubMed  Google Scholar 

  10. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F (1990) An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 86:1343–1346

    CAS  PubMed  Google Scholar 

  11. Hubert C, Houot A-M, Corvol P, Soubrier F (1991) Structure of the angiotensin I-converting enzyme gene. Two alternate promoters correspond to evolutionary steps of a duplicated gene. J Biol Chem 266:15377–15383

    CAS  PubMed  Google Scholar 

  12. Rigat B, Hubert C, Corvol P, Soubrier F (1992) PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase 1). Nucleic Acids Res 20:1433

    CAS  Google Scholar 

  13. Cambien F, Alhenc-Gelas F, Herbeth B, Andre JL, Rakotovao R, Gonzales MF, Allegrini J, Bloch C (1988) Familial resemblance of plasma angiotensin-converting enzyme level: The Nancy Study. Am J Hum Genet 43:774–780

    CAS  PubMed  Google Scholar 

  14. Costerousse O, Allegrini J, Lopez M, Alhenc-Gelas F (1993) Angiotensin I-converting enzyme in human circulating mononuclear cells: genetic polymorphism of expression in T-lymphocytes. Biochem J 290:33–40

    CAS  PubMed  Google Scholar 

  15. Solini A, Dalla Vestra M, Saller A, Nosadini R, Crepaldi G, Fioretto P (2002) The angiotensin-converting enzyme DD genotype is associated with glomerulopathy lesions in type 2 diabetes. Diabetes 51:251–255

    CAS  PubMed  Google Scholar 

  16. Hadjadj S, Belloum R, Bouhanick B, Gallois Y, Guilloteau G, Chatellier G, Alhenc-Gelas F, Marre M (2001) Prognostic value of angiotensin-I converting enzyme I/D polymorphism for nephropathy in type 1 diabetes mellitus: a prospective study. J Am Soc Nephrol 12:541–549

    CAS  PubMed  Google Scholar 

  17. Hohenfellner K, Hunley TE, Brezinska R, Brodhag P, Shyr Y, Brenner W, Habermehl P, Kon V (1999) ACE I/D gene polymorphism predicts renal damage in congenital uropathies. Pediatr Nephrol 13:514–518

    CAS  PubMed  Google Scholar 

  18. Al-Eisa A, Haider MZ, Srivastava BS (2000) Angiotensin-converting enzyme gene insertion/deletion polymorphism and renal damage in childhood uropathies. Pediatr Int 42:348–353

    Article  CAS  PubMed  Google Scholar 

  19. Curnow KM, Pascoe L, White PC (1992) Genetic analysis of the human type-1 angiotensin II receptor. Mol Endocrinol 6:113–118

    Article  Google Scholar 

  20. Bonnardeaux A, Davies E, Jeunemaitre X, Fery I, Charru A, Clauser E, Tiret L, Cambien F, Corvol P, Soubrier F (1994) Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension 24:63–69

    CAS  PubMed  Google Scholar 

  21. Matsusaka T, Ichikawa I (1997) Biological functions of angiotensin and its receptors. Annu Rev Physiol 59:395–412

    Article  CAS  PubMed  Google Scholar 

  22. Kunkel LM, Smith KD, Boyer SH, Borgankar DS, Wachtel SS, Miller OJ, Beg WR, Jones HW, Rary JM (1977) Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants. Proc Natl Acad Sci U S A 74:1245–1249

    CAS  PubMed  Google Scholar 

  23. Stanković A, Ilić N, Žunić Z, Glišić S, Alavantić D (1999) Association of insertion/deletion polymorphism at the angiotensin I-converting enzyme locus with arterial blood pressure. Jugoslov Med Biohem 18:141–147

    Google Scholar 

  24. Lindpaintner K, Pfeffer MA, Kreutz R, Stampfer MJ, Grodstein F, LaMotte F, Buring J, Hennekens CH (1995) A prospective evaluation of an angiotensin-converting-enzyme gene polymorphism and the risk of ischemic heart disease. N Engl J Med 332:706–711

    CAS  PubMed  Google Scholar 

  25. Stanković A, Alavantić D (2002) Rapid detection of the hypertension associated A1166C polymorphism of the angiotensin II type 1 receptor. Genet Test 6:133–134

    Article  PubMed  Google Scholar 

  26. Haszon I, Friedman AL, Papp F, Bereczki C, Baji S, Bodrogi T, Karoly E, Endreffy E, Turi S (2002) ACE gene polymorphism and renal scarring in primary vesicoureteric reflux. Pediatr Nephrol 17:1027–1031

    Article  PubMed  Google Scholar 

  27. Brock JW, Adams M, Hunley T, Wada A, Trusler L, Kon V (1997) Potential risk factors associated with progressive renal damage in childhood urological diseases—the role of angiotensin-converting enzyme gene polymorphism. J Urol 158:1308–1311

    PubMed  Google Scholar 

  28. Ozen S, Alikasifoglu M, Saatci U, Bakkaloglu A, Besbas N, Kara N, Kocak H, Erbas B, Unsal I, Tuncbilek E (1999) Implications of certain genetic polymorphisms in scarring in vesicoureteric reflux: importance of ACE polymorphism. Am J Kidney Dis 34:140–145

    CAS  PubMed  Google Scholar 

  29. Lai KN, Leung JCK, Lai KB, To WY, Yeung VTF, Lai FMM (1998) Gene expression of the renin-angiotensin system in human kidney. J Hypertens 16:91–102

    CAS  PubMed  Google Scholar 

  30. Mizuiri S, Hemmi H, Kumanomidou H, Iwamoto M, Miyagi M, Sakai K, Aikawa A, Ohara T, Yamada K, Shimatake H, Hasegawa A (2001) Angiotensin-converting enzyme (ACE) I/D genotype and renal ACE gene expression. Kidney Int 60:1124–1130

    Article  CAS  PubMed  Google Scholar 

  31. Bonnardeaux A, Davies E, Jeunemaitre X, Fery I, Charru A, Clauser E, Tiret L, Cambien F, Corvol P, Soubrier F (1994) Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension 24:63–69

    CAS  PubMed  Google Scholar 

  32. Stanković A, Živković M, Glišić S, Alavantić D (2003) Angiotensin II type 1 receptor gene polymorphism and essential hypertension in Serbian population. Clin Chim Acta 327:181–185

    Article  PubMed  Google Scholar 

  33. Doria A, Onuma T, Warram JH, Krolewski AS (1997) Synergistic effect of angiotensin II type 1 receptor genotype and poor glycaemic control on risk of nephropathy in IDDM. Diabetologia 40:1293–1299

    Article  CAS  PubMed  Google Scholar 

  34. Tarnow L, Cambien F, Rossing P, Nielsen FS, Hansen BV, Ricard S, Poirer O, Parving HH (1996) Angiotensin-II type 1 receptor gene polymorphism and diabetic microangiopathy. Nephrol Dial Transplant 11:1019–1023

    CAS  PubMed  Google Scholar 

  35. Hohenfellner K, Hunley TE, Yerkes E, Habermehl P, Hohenfellner R, Kon V (1999) Angiotensin II, type 2 receptor in the development of vesico-ureteric reflux. BJU Int 83:318–322

    CAS  PubMed  Google Scholar 

  36. Hohenfellner K, Hunley TE, Schloemer C, Brenner W, Yerkes E, Zepp F, Brock JW 3rd, Kon V (1999) Angiotensin type 2 receptor is important in the normal development of the ureter. Pediatr Nephrol 13:187–191

    CAS  PubMed  Google Scholar 

  37. Pardo R, Malaga S, Coto E, Navarro M, Alvarez V, Espinosa L, Alvarez R, Vallo A, Loris C, Braga S (2003) Renin-angiotensin system polymorphisms and renal scarring. Pediatr Nephrol 18:110–114

    PubMed  Google Scholar 

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Acknowledgement

This study was supported by Government Research grants 2011 and 1901.

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Authors and Affiliations

  1. University Children’s Hospital, Belgrade, Serbia and Montenegro

    Mirjana Kostić, Amira Peco-Antić, Olga Jovanović & Divna Kruščić

  2. Laboratory for Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences, Belgrade, Serbia and Montenegro

    Aleksandra Stanković, Maja Živković & Dragan Alavantić

  3. Laboratory for Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences, P.O. Box 522, 11001 Belgrade, Serbia and Montenegro

    Dragan Alavantić

Authors
  1. Mirjana Kostić
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  2. Aleksandra Stanković
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  3. Maja Živković
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  4. Amira Peco-Antić
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  5. Olga Jovanović
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  6. Dragan Alavantić
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  7. Divna Kruščić
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Corresponding author

Correspondence to Dragan Alavantić.

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M. Kostić and A. Stanković contributed equally to this work

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Kostić, M., Stanković, A., Živković, M. et al. ACE and AT1 receptor gene polymorphisms and renal scarring in urinary bladder dysfunction. Pediatr Nephrol 19, 853–857 (2004). https://doi.org/10.1007/s00467-004-1511-3

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  • DOI: https://doi.org/10.1007/s00467-004-1511-3

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