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Transforming growth factor-β in diabetic nephropathy

Abstract

Background

Renal failure is a common and serious complication of long-standing diabetes mellitus. Diabetes is the most common cause of end-stage renal failure. Transforming growth factor-β (TGF-β) is one of the major growth factors involved in extracellular matrix accumulation in fibrotic disorders including diabetic nephropathy.

Aim of the work

The aim of the present study was to evaluate the serum level of TGF-β as a marker for the development and progression of diabetic nephropathy.

Patients and methods

This work included 40 patients with diabetes and 40 healthy controls with matched age and sex. Individuals with diabetes included 25 patients with type 2 diabetes and 15 with type 1 diabetes. We considered the presence of hypertension, use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, and the degree of proteinuria. All patients were subjected to careful history taking, thorough physical examinations, and fundus examination. Routine laboratory tests such as analysis of complete blood count and determination of erythrocyte sedimentation rate were carried out to rule out patients with malignancy or autoimmune disease. Kidney function tests (blood urea and serum creatinine), complete urine analysis, and estimation of 24-h urinary protein or albumin, creatinine clearance, blood glucose measurement (fasting and 2h postprandial), serum TGF-β level, and microalbuminuria were also carried out.

Results

The serum levels of TGF-β were statistically significantly higher in patients with diabetes compared with normal healthy people. The serum TGF-β level was statistically significantly higher in patients with diabetes with overt nephropathy compared with those without it. There was a statistically significant decrease in TGF-β levels in patients with diabetes who were taking angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers compared with those who were not taking such medications.

Conclusion

Serum TGF-β level increases in patients of both type 1 and type 2 diabetes and in those with diabetic nephropathy. TGF-β is considered one of the major mediators of diabetic renal fibrogenesis that results in end-stage renal disease.

References

  1. Lan S, Vander Geest RN, Verhagen NA, Van Nieuwenhoven FA, Blom IE, Aten J, et al. Connective tissue growth factor and IGF-1 are produced by human renal fibroblasts and cooperate in the induction of collagen production by high glucose. Diabetes 2003; 52:2975–2983.

    Article  Google Scholar 

  2. Kobayashi T, Okada H, Inoue T, Kanno Y, Suzuki H. Tubular expression of connective tissue growth factor correlates with interstitial fibrosis in type 2 diabetic nephropathy. Nephrol Dial Transplant 2006; 21:548–549.

    Article  Google Scholar 

  3. Holmquist P, Sjobald S, Torfffvit O. Pore size and charge selectivity of the glomerular membrane at the time of diagnosis of diabetes. Pediatr Nephrol 2004; 1:1361–1366.

    Article  Google Scholar 

  4. Kim SJ, Im YH, Markowitz SD, Bang YJ. Molecular mechanisms of inactivation of TGF-β receptors during carcinogenesis. Cytokine Growth Factor Rev 2005; 11:159–168.

    Article  Google Scholar 

  5. Brigstock DR. Strategies for blocking the fibrogenic actions of connective tissue growth factor: from pharmacological inhibition in vitro to targeted siRNA therapy in vivo. J Cell Commun Signal 2009; 3:5–18.

    Article  Google Scholar 

  6. Wang X, Shaw S, Amiri F, Eaton DC, Marrero MB. Inhibition of the Jak/STAT signaling pathway prevents the high glucose-induced increase in TGF-beta and fibronectin synthesis in mesangial cells. Diabetes 2002; 51: 3505–3509.

    CAS  Article  Google Scholar 

  7. Gracia-Sanchezo O, Lopez-Hernandez FJ, Lopez-Novoa JM. Transforming growth factor-beta is acytokin participate in several processes. Kidney Int 2010; 77:950.

    Article  Google Scholar 

  8. Svensson M, Sundkvist G, Arnqvist HJ, Bjork E, Blohme G, Bolinder J, et al. Diabetes incidence study in Sweden (DISS): signs of nephropathy may occur early in young adults with diabetes despite modern diabetes management. Diabetes Care 2003; 26:2903–2909.

    Article  Google Scholar 

  9. Schena FP, Gesualdo L. Pathogenic mechanisms of diabetic nephropathy. J Am Soc Nephrol 2005; 16 (Suppl 1): S30–S33.

    CAS  Article  Google Scholar 

  10. Fioretto P, Steffes MW, Brown DM, Mauer SM. An overview of renal pathology in insulin-dependent diabetes mellitus in relationship to altered glomerular hemodynamics. Am J Kidney Dis 2001; 20:549–558.

    Article  Google Scholar 

  11. Montero A, Munger KA, Khan RZ, Valdivielso JM, Morrow JD, Guash A, et al. F (2)-isoprostanes mediate high glucose-induced TGF-β synthesis and glomerular proteinuria in experimental type I diabetes. Kidney Int 2000; 58:1963–1972.

    CAS  Article  Google Scholar 

  12. Ziyadeh FN. Mediators of diabetic renal disease, the case for TGF-β as the major mediator. J Am Soc Nephrol 2004; 15:S55–S57.

    CAS  Article  Google Scholar 

  13. Hellmich B, Schellner M, Schatz H, Pfeiffer A. Activation of transforming growth factor-β1 in diabetic kidney disease. Metabolism 2000; 49:353–359.

    CAS  Article  Google Scholar 

  14. Tesfaye S, Malik Vascular R, Ward JD. Factors in diabetic neuropathy. Diabetologia 2002; 37:847–854.

    Article  Google Scholar 

  15. Isono M, Chen S, Iglesias-de la Cruz MC, Hong SW, Ziyadeh FN. Smad pathway is activated in the diabetic mouse kidney and Smad3 mediates TGF-beta induced fibronectin in mesangial cells. Biochem Biophys Res Commun 2002; 296:1356–1365.

    CAS  Article  Google Scholar 

  16. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001; 414:813–820.

    CAS  Article  Google Scholar 

  17. Ardura JA, Berruguete R, Rámila D, Alvarez-Arroyo MV, Esbrit P. Parathyroid hormone-related protein interacts with vascular endothelial growth factor to promote fibrogenesis in the obstructed mouse kidney. Am J Physiol Renal Physiol 2008; 295:F415–F425.

    CAS  Article  Google Scholar 

  18. Sheets MJ, King GL. Molecular understanding of hyperglycemia’s adverse effects for diabetic complications. JAMA 2002; 288:2579–2588.

    Article  Google Scholar 

  19. Van den Heuvel M, Batenburg WW, Danser AHJ. Diabetic complications: a role for the prorenin-(pro)renin receptor-TGF-β1 axis? Mol Cell Endocrinol 2009; 302:213–218.

    Article  Google Scholar 

  20. Weigert C, Brodbeck K, Klopfer K, Haring HU, Schleicher ED. Angiotensin II induces human TGF-beta promoter activation: similarity to hyperglycaemia. Diabetologia 2002; 45:890–898.

    CAS  Article  Google Scholar 

  21. Jacobsen P, Andersen S, Jensen BR, Parving HH. Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy. J Am Soc Nephrol 2003; 14:992–999.

    CAS  Article  Google Scholar 

  22. Kakoki M, Takahashi N, Jennette JC, Smithies O. Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor. Proc Natl Acad Sci USA 2004; 104:13302–13305.

    Article  Google Scholar 

  23. Villa L, Boor P, Konieczny A, Kunter U, van Roeyen CR, Denecke B, et al. Effects and mechanisms of angiotensin II receptor blockade with telmisartan in a normotensive model of mesangioproliferative nephritis. Nephrol Dial Transplant 2011; 26:3131–3143.

    CAS  Article  Google Scholar 

  24. Viberti G, Wheeldon NM. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation 2002; 106:672–678.

    CAS  Article  Google Scholar 

  25. Ruiz-Ortega M, Lorenzo O4, Dandona P, Dhindsa S, Ghanim H, Chaudhuri A. Angiotensin II and inflammation: the effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade. J Hum Hypertens 2007; 21:20–27.

    Article  Google Scholar 

  26. Caramory M, Fioretto P, Mauer M. The need for early predictors of diabetic nephropathy risk: is albumin excretion rate is sufficient? Diabetes 2000; 49:1399–1408.

    Article  Google Scholar 

  27. American Diabetes Association. Diabetic nephropathy. Diabetes Care 2007; 27:S79–S80.

    Google Scholar 

  28. Pham TT, Sim JJ, Kujubu DA, Liu IK, Kumar VA. Prevalence of non diabetic renal disease in diabetic patients. Am J Nephrol 2007; 27:322.

    Article  Google Scholar 

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Correspondence to Karima Y. Ahmed.

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Ahmed, K.Y., El-Bazz, W.F., Mohamed, H.A. et al. Transforming growth factor-β in diabetic nephropathy. Egypt J Intern Med 25, 20–26 (2013). https://doi.org/10.7123/01.EJIM.0000425960.41858.d5

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  • DOI: https://doi.org/10.7123/01.EJIM.0000425960.41858.d5

Keywords

  • angiotensin-converting enzyme inhibitors
  • angiotensin II receptor blockers
  • diabetic nephropathy
  • transforming growth factor-β