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. 2005 Jul;66(4):266–278. doi: 10.1016/j.curtheres.2005.08.003

Role of transforming growth factor-β2 in, and apossible transforming growth factor-β2 gene polymorphism as a marker of, renal dysfunction in essential hypertension: A study in Turkish patients

Zerrin Bicik 1, Sevim Gönen 2, Talat Bahçebasi 3, Kadriye Reis 2, Turgay Arinsoy 2, Sükrü Sindel 2
PMCID: PMC3964570  PMID: 24672129

Abstract

Background:

Many studies have shown that transforming growth factor(TGF)-β has a major role in renal scarring in many renal diseases and hypertension.

Objectives:

The primary aim of this study was to investigate both the relationship between hypertension and serum and urinary levels of TGF-β2 (a more sensitive isoform for glomeruli than TGF-β1), and the effects of combination therapy with perindopril + indapamide on microalbuminuria, which becomes an early indicator of hypertensive benign nephropathy, and serum and urinary TGF-β2 levels in patients with mild to moderate essential hypertension. In addition, we examined the possible relationship between TGF-β2 gene polymorphism and essential hypertension.

Methods:

This study was conducted at the Department of Nephrology, Medical Faculty, Gazi University, Ankara, Turkey. Patients aged ≥18 years with newly diagnosed mild to moderate essential hypertension (systolic/diastolic blood pressure [SBP/DBP] >120/>80 mm Hg) who had not previously received antihypertensive treatment were included in the study. Patients with stage I hypertension received perindopril 2 mg + indapamide 0.625 mg (tablet), and patients with stage lI hypertension received perindopril 4 mg + indapamide 1.125 mg (tablet). All study drugs were given OD (morning) PO with food for 6 months. Serum and urinary TGF-β2 and creatinine levels and serum and urinary albumin levels were measured before and after perindopril + indapamide administration. Amplified DNA fragments of the TGF-β2 primer region were screened using amplification refractory mutation system polymerase chain reaction analysis, and the number of ACA repeats was confirmed by DNA sequencing. Genetic studies were performed using a commercial TGF-β2 kit.

Results:

Forty patients were enrolled in the study, and 38 patients (27 women, 11 men; mean [SD] age, 46.3 [6.5] years) completed it. SBP and DBP were significantly decreased from baseline with perindopril/indapamide (both, P < 0.001). Microalbuminuria and urinary TGF-β2 levels also decreased significantly from baseline (P = 0.04 and P < 0.001, respectively), whereas the serum TGF-β2 level did not change significantly. Three patients, all of whom were found to have TGF-β2 gene mutations, had increased urinary TGF-β2 levels despite good blood pressure control.

Conclusions:

The results of this study in patients with mild to moderate hypertension suggest that, despite good clinical control of blood pressure, the persistence of microalbuminuria and high urinary TGF-β2 levels might predict renal impairment. When treating these patients, genetic tendencies and possible polymorphisms on the TGF-β2 locus should be kept in mind.

Keywords: hypertension, perindopril, indapamide, microalbuminuria, TGF-β2, gene polymorphism

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References

  • 1.Kaplan N.M. 7th ed. Lippincott Williams & Wilkins; Baltimore, Md: 1998. Primary Hypertension: Pathogenesis in Clinical Hypertension; pp. 41–88. [Google Scholar]
  • 2.el Nahas A.M. Renal scarring: The role of angiotensin II. Nephrol Dial Transplant. 1995;10:28–32. [PubMed] [Google Scholar]
  • 3.Bigazzi R., Bianchi S., Baldari D., Campese V.M. Microalbuminuria predicts cardiovascular events and renal insufficiency in patients with essential hypertension. J Hypertens. 1998;16:1325–1333. doi: 10.1097/00004872-199816090-00014. [DOI] [PubMed] [Google Scholar]
  • 4.Damsgaard E.M., Froland A., Jorgensen O.D., Mogensen C.E. Microalbuminuria as predictor of increased mortality in elderly people. BMJ. 1990;300:297–300. doi: 10.1136/bmj.300.6720.297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Mikhail N., Fukuda N., Tremblay J., Hamet P. Platelets, growth factors, and vascular smooth-muscle cells in hypertension and diabetes. J Cardiooasc Pharmacol. 1993;22(Suppl 6):564–574. [PubMed] [Google Scholar]
  • 6.Baroni E.A., Costa R.S., Volpini R., Coimbra T.M. Sodium bicarbonate treatment reduces renal injury, renal production of transforming growth factor-beta, and urinary transforming growth factor-betaexcretion in rats with doxorubicin-induced nephropathy. Am J Kidney Dis. 1999;34:328–337. doi: 10.1016/s0272-6386(99)70363-x. [DOI] [PubMed] [Google Scholar]
  • 7.De Albuquerque D.A., Saxena V., Adams D.E. An ACE inhibitor reduces Th2 cytokines and TGF-betal and TGF-beta2 isoforms in murine lupus nephritis. Kidney Int. 2004;66:869. doi: 10.1111/j.1523-1755.2004.00462.x. Letter. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Daopin S., Piez K.A., Ogawa Y., Davies D.R. Crystal structure of transforming growth factor-beta 2: An unusual fold for the superfamily. Science. 1992;257:369–373. doi: 10.1126/science.1631557. [DOI] [PubMed] [Google Scholar]
  • 9.Sharma K., Ziyadeh F.N. The transforming growth factor-beta system and the kidney. Semin Nephrol. 1993;13:116–128. [PubMed] [Google Scholar]
  • 10.Border W.A., Ruoslahti E. Transforming growth factor-beta in disease: The dark side of tissue repair. J Clin Invest. 1992;90:1–7. doi: 10.1172/JCI115821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Sharma K., Ziyadeh F.N. The emerging role of transforming growth factor-beta in kidney diseases. Am J Physiol. 1994;266:F829–F842. doi: 10.1152/ajprenal.1994.266.6.F829. [DOI] [PubMed] [Google Scholar]
  • 12.Senior K. The complex puzzle of gene variation and essential hypertension. Mol Med Today. 1999;5:506. doi: 10.1016/s1357-4310(99)01606-8. [DOI] [PubMed] [Google Scholar]
  • 13.Ertürk S. Presented at the National Hypertension & Renal Diseases Congress. 2004. Treatment aspect in non-compliant patients, 6. June 2–6. Belek/Antalya, Turkey. [Google Scholar]
  • 14.Turkish Cardiology Association . TCA; Istanbul, Turkey: 2000. National Guide of Hypertension Treatment and Follow-Up. [Google Scholar]
  • 15.The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997;157:2413–2446. doi: 10.1001/archinte.157.21.2413. [published correction appears in Arch Intern Med. 1998;158:573] [DOI] [PubMed] [Google Scholar]
  • 16.Nishimura D.Y., Purchio A.F., Murray J.C. Linkage localisation of TGF-β2 and the human homeobox gene HLX1 to chromosome 1q. Genomics. 1993;15:357–364. doi: 10.1006/geno.1993.1068. [DOI] [PubMed] [Google Scholar]
  • 17.United Kingdom Prospective Diabetes Study Group Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:703–713. [published correction appears in BMJ 1999;318:29] [PMC free article] [PubMed] [Google Scholar]
  • 18.PROGRESS Collaborative Group Randomised trial of a perindopril-based bloodpressure-lowering regimen among 6,105 individuals with previous stroke ortransient ischaemic attack. Lancet. 2001;358:1033–1041. doi: 10.1016/S0140-6736(01)06178-5. [published corrections appear in Lancet. 2001;358:1556 and Lancet. 2002;359:2120]. [DOI] [PubMed] [Google Scholar]
  • 19.Hadrava V., Kruppa U., Russo R.C. Vascular smooth muscle cell proliferation and its therapeutic modulation in hypertension. Am Heart J. 1991;122:1198–1203. doi: 10.1016/0002-8703(91)90939-f. [DOI] [PubMed] [Google Scholar]
  • 20.Zarif L., Covic A., Iyengar S. Inaccuracy of clinical phenotyping parameters for hypertensive nephrosclerosis. Nephrol Dial Transplant. 2000;15:1801–1807. doi: 10.1093/ndt/15.11.1801. [DOI] [PubMed] [Google Scholar]
  • 21.Tsioufis C., Tzioumis C., Marinakis N. Microalbuminuria is closely related to impaired arterial elasticity in untreated patients with essential hypertension. Nephron Clin Pract. 2003;93:c106–c111. doi: 10.1159/000069546. [DOI] [PubMed] [Google Scholar]
  • 22.Ray P.E., McCune B., Gomez R.A. Induction of transforming growth factor-beta 2–3 in the juxtaglomerular apparatus and renal vascular smooth muscle cells of young rats and infants. Exp Nephrol. 1994;2:129. Letter. [PubMed] [Google Scholar]
  • 23.Burrow C.R. Regulatory molecules in kidney development. Pediatr Nephrol. 2000;14:240–253. doi: 10.1007/s004670050049. [DOI] [PubMed] [Google Scholar]
  • 24.Cambien F., Ricard S., Troesch A. Polymorphisms of the transforming growth factor-beta 1 gene in relation to myocardial infarction and blood pressure. Hypertension. 1996;28:881–887. doi: 10.1161/01.hyp.28.5.881. for the Etude Cas-Temoin de l'Infarctus du Myocarde (ECTIM) Study. [DOI] [PubMed] [Google Scholar]
  • 25.Li B., Khanna A., Sharma V. TGF-betal DNA polymorphisms, protein levels, and blood pressure. Hypertension. 1999;33:271–275. doi: 10.1161/01.hyp.33.1.271. [DOI] [PubMed] [Google Scholar]
  • 26.August P., Suthanthiran M. Transforming growth factor beta and progression of renal disease. Kidney Int Suppl. 2003;87:S99–S104. doi: 10.1046/j.1523-1755.64.s87.15.x. [DOI] [PubMed] [Google Scholar]
  • 27.Yu L., Border W.A., Huang Y., Noble N.A. TGF-beta isoforms in renal fibrogenesis. Kidney Int. 2003;64:844–856. doi: 10.1046/j.1523-1755.2003.00162.x. [DOI] [PubMed] [Google Scholar]
  • 28.Pfeilschifter J., Pignat W., Leighton J. Transforming growth factor beta 2 differentially modulates interleukin-1 beta-and tumour-necrosis-factor-alpha-stimulated phospholipase A2 and prostaglandin E2 synthesis in rat renal mesangial cells. Biochem J. 1990;270:269–271. doi: 10.1042/bj2700269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Pfeilschifter J., Vosbeck K. Transforming growth factor beta 2 inhibits interleukin 1 beta- and tumor necrosis factor alpha-induction of nitric oxide synthase in rat renal mesangial cells. Biochem Biophys Res Commun. 1991;175:372–379. doi: 10.1016/0006-291x(91)91574-v. [DOI] [PubMed] [Google Scholar]
  • 30.London G.M., Asmar R.G., O'Rourke M.E., Safar M.E. Program and abstracts of the 11th European Meeting on Hypertension. 2001. Improvement in large artery mechanical properties with the very low dose perindopril/indapamide combination The Reason Project. June 15–19. Milan, Italy. Abstract PS 20/193. [Google Scholar]
  • 31.Wong W., Singh A.K. Urinary cytokines: Clinically useful markers of chronic renal disease progression? Curr Opin Nephrol Hypertens. 2001;10:807–811. doi: 10.1097/00041552-200111000-00012. [DOI] [PubMed] [Google Scholar]
  • 32.Freedman B.I., Yu H., Spray B.J. Genetic linkage analysis of growth factor loci and end-stage renal disease in African Americans. Kidney Int. 1997;51:819–825. doi: 10.1038/ki.1997.115. [DOI] [PubMed] [Google Scholar]
  • 33.Alansari A., Hajeer A.H., Bayat A. Two novel polymorphisms in the human transforming growth factor beta 2 gene. Genes Immun. 2001;2:295–296. doi: 10.1038/sj.gene.6363780. [DOI] [PubMed] [Google Scholar]

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