Advertisement

Journal of Cell Communication and Signaling

, Volume 5, Issue 3, pp 193–200 | Cite as

CCN-2 is up-regulated by and mediates effects of matrix bound advanced glycated end-products in human renal mesangial cells

  • Xiaoyu Wang
  • Susan V. McLennan
  • Stephen M. TwiggEmail author
Research Article

Abstract

CCN-2, also known as connective tissue growth factor (CCN-2/CTGF) is a cysteine rich, extracellular matrix protein that acts as a pro-fibrotic cytokine in tissues in many diseases, including in diabetic nephropathy. We have published that soluble advanced glycation end products (AGEs), that are present in increased amounts in diabetes, induce CCN-2. However in vivo AGEs are known to be heavily tissue bound and whether matrix bound AGEs regulate CCN-2 has not been investigated. In this study we determined in human renal mesangial cells if CCN-2 is induced by matrix associated AGEs and if CCN-2 may then secondarily mediate effects of matrix AGEs on extracellular matrix expansion. Data generated show that CCN-2 mRNA and protein expression are induced by matrix bound AGEs, and in contrast, this was not the case for TGF-β1 mRNA regulation. Using CCN-2 adenoviral anti-sense it was found that CCN-2 mediated the up-regulation of fibronectin and the tissue inhibitor of matrix metalloproteinase, TIMP-1, that was caused by matrix bound AGEs. In conclusion, CCN-2 is induced by non-enzymatically glycated matrix and it mediates downstream fibronectin and TIMP-1 increases, thus through this mechanism potentially contributing to ECM accumulation in the renal glomerulus in diabetes.

Keywords

CCN-2 Diabetic nephropathy Advanced glycation Matrix CTGF 

Notes

Acknowledgements

This study was supported by Project Grant #402559 from the National Health and Medical Research Council (NHMRC) of Australia and by the Endocrinology and Diabetes Research Foundation, The University of Sydney.

References

  1. Adler SG, Kang SW, Feld S, Cha DR, Barba L, Striker L, Striker G, Riser BL, LaPage J, Nast CC (2001) Glomerular mRNAs in human type 1 diabetes: biochemical evidence for microalbuminuria as a manifestation of diabetic nephropathy. Kidney Int 60:2330–6PubMedCrossRefGoogle Scholar
  2. Adler SG, Kang SW, Feld S, Cha DR, Barba L, Striker L, Striker G, Riser BL, LaPage J, Nast CC (2002) Can glomerular mRNAs in human type 1 diabetes be used to predict transition from normoalbuminuria to microalbuminuria? Am J Kidney Dis 40:184–8PubMedCrossRefGoogle Scholar
  3. Adler SG, Schwartz S, Williams ME, Arauz-Pacheco C, Bolton WK, Lee T, Li D, Neff TB, Urquilla PR, Sewell KL (2010) Phase 1 study of anti-CTGF monoclonal antibody in patients with diabetes and microalbuminuria. Clin J Am Soc Nephrol 5:1420–8PubMedCrossRefGoogle Scholar
  4. Beisswenger PJ, Makita Z, Curphey TJ, Moore LL, Jean S, Brinck-Johnsen T, Bucala R, Vlassara H (1995) Formation of immunochemical advanced glycosylation end products precedes and correlates with early manifestations of renal and retinal disease in diabetes. Diabetes 44:824–829PubMedCrossRefGoogle Scholar
  5. Berlanga J, Cibrian D, Guillen I, Freyre F, Alba JS, Lopez-Saura P, Merino N, Aldama A, Quintela AM, Triana ME, Montequin JF, Ajamieh H, Urquiza D, Ahmed N, Thornalley PJ (2005) Methylglyoxal administration induces diabetes-like microvascular changes and perturbs the healing process of cutaneous wounds. Clin Sci (Lond) 109:83–95CrossRefGoogle Scholar
  6. Bierhaus A, Hofmann MA, Ziegler R, Nawroth PP (1998) AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept. Cardiovasc Res 37:586–600PubMedCrossRefGoogle Scholar
  7. Brooks BA, Franjic B, Ban CR, Swaraj K, Yue DK, Celermajer DS, Twigg SM (2008) Diastolic dysfunction and abnormalities of the microcirculation in type 2 diabetes. Diabetes Obes Metab 10:739–46PubMedCrossRefGoogle Scholar
  8. Burns WC, Twigg SM, Forbes JM, Pete J, Tikellis C, Thallas-Bonke V, Thomas MC, Cooper ME, Kantharidis P (2006) Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition: implications for diabetic renal disease. J Am Soc Nephrol 17:2484–94PubMedCrossRefGoogle Scholar
  9. Candido R, Forbes JM, Thomas MC, Thallas V, Dean RG, Burns WC, Tikellis C, Ritchie RH, Twigg SM, Cooper ME, Burrell LM (2003) A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes. Circ Res 92:785–92PubMedCrossRefGoogle Scholar
  10. Chiarelli F, de Martino M, Mezzetti A, Catino M, Morgese G, Cuccurullo F, Verrotti A (1999) Advanced glycation end products in children and adolescents with diabetes: relation to glycemic control and early microvascular complications. J Pediatr Endocrinol Metab 134:486–491Google Scholar
  11. Chung AC, Zhang H, Kong YZ, Tan JJ, Huang XR, Kopp JB, Lan HY (2009) Advanced glycation end-products induce tubular CTGF via TGF-beta-independent Smad3 signaling. J Am Soc Nephrol 21:249–60PubMedCrossRefGoogle Scholar
  12. Cooper ME (1998) Pathogenesis, prevention, and treatment of diabetic nephropathy. Lancet 352:213–9PubMedCrossRefGoogle Scholar
  13. Gauer S, Segitz V, Goppelt-Struebe M (2007) Aldosterone induces CTGF in mesangial cells by activation of the glucocorticoid receptor. Nephrol Dial Transplant 22:3154–9PubMedCrossRefGoogle Scholar
  14. Guha M, Xu ZG, Tung D, Lanting L, Natarajan R (2007) Specific down-regulation of connective tissue growth factor attenuates progression of nephropathy in mouse models of type 1 and type 2 diabetes. FASEB J 21:3355–68PubMedCrossRefGoogle Scholar
  15. King GL, Wakasaki H (1999) Theoretical mechanisms by which hyperglycemia and insulin resistance could cause cardiovascular diseases in diabetes. Diabetes Care 22:C31–C37PubMedGoogle Scholar
  16. Krishnamurti U, Rondeau E, Sraer JD, Michael AF, Tsilibary EC (1997) Alterations in human glomerular epithelial cells interacting with nonenzymatically glycosylated matrix. J Biol Chem 272:27966–70PubMedCrossRefGoogle Scholar
  17. Lee CI, Guh JY, Chen HC, Lin KH, Yang YL, Hung WC, Lai YH, Chuang LY (2004) Leptin and connective tissue growth factor in advanced glycation end-product-induced effects in NRK-49F cells. J Cell Biochem 93:940–50PubMedCrossRefGoogle Scholar
  18. Lee CI, Guh JY, Chen HC, Hung WC, Yang YL, Chuang LY (2005) Advanced glycation end-product-induced mitogenesis and collagen production are dependent on angiotensin II and connective tissue growth factor in NRK-49F cells. J Cell Biochem 95:281–92PubMedCrossRefGoogle Scholar
  19. Lehmann R, Schleicher ED (2000) Molecular mechanism of diabetic nephropathy. Clin Chim Acta 297:135–44PubMedCrossRefGoogle Scholar
  20. Liu N, Shimizu S, Ito-Ihara T, Takagi K, Kita T, Ono T (2007) Angiotensin II receptor blockade ameliorates mesangioproliferative glomerulonephritis in rats through suppression of CTGF and PAI-1, independently of the coagulation system. Nephron Exp Nephrol 105:e65–74PubMedCrossRefGoogle Scholar
  21. Mason RM, Wahab NA (2003) Extracellular matrix metabolism in diabetic nephropathy. J Am Soc Nephrol 14:1358–73PubMedCrossRefGoogle Scholar
  22. McLennan SV, Fisher EJ, Yue DK, Turtle JR (1994) High glucose concentration causes a decrease in mesangium degradation: a factor in the pathogenesis of diabetic nephropathy. Diabetes 43:1041–1045PubMedCrossRefGoogle Scholar
  23. McLennan SV, Martell SK, Yue DK (2002) Effects of mesangium glycation on matrix metalloproteinase activities: possible role in diabetic nephropathy. Diabetes 51:2612–2618PubMedCrossRefGoogle Scholar
  24. McLennan SV, Wang XY, Moreno V, Yue DK, Twigg SM (2004) Connective tissue growth factor mediates high glucose effects on matrix degradation through tissue inhibitor of matrix metalloproteinase type 1: implications for diabetic nephropathy. Endocrinology 145:5646–55PubMedCrossRefGoogle Scholar
  25. McLennan SV, Kelly DJ, Schache M, Waltham M, Dy V, Langham RG, Yue DK, Gilbert RE (2007) Advanced glycation end products decrease mesangial cell MMP-7: a role in matrix accumulation in diabetic nephropathy? Kidney Int 72:481–8PubMedCrossRefGoogle Scholar
  26. Murphy M, Godson C, Cannon S, Kato S, Mackenzie HS, Martin F, Brady HR (1999) Suppression subtractive hybridization identifies high glucose levels as a stimulus for expression of connective tissue growth factor and other genes in human mesangial cells. J Biol Chem 274:5830–4PubMedCrossRefGoogle Scholar
  27. Nakamura T, Fukui M, Ebihara I, Osada S, Tomino Y, Koide H (1994) Abnormal gene expression of matrix metalloproteinases and their inhibitors in glomeruli from diabetic rats. Renal Physiol Biochem 17:316–325PubMedGoogle Scholar
  28. Nathan DM, Zinman B, Cleary PA, Backlund JY, Genuth S, Miller R, Orchard TJ (2009) Modern-day clinical course of type 1 diabetes mellitus after 30 years’ duration: the diabetes control and complications trial/epidemiology of diabetes interventions and complications and Pittsburgh epidemiology of diabetes complications experience (1983–2005). Arch Intern Med 169:1307–16PubMedCrossRefGoogle Scholar
  29. Park SK, Kim J, Seomun Y, Choi J, Kim DH, Han IO, Lee EH, Chung SK, Joo CK (2001) Hydrogen peroxide is a novel inducer of connective tissue growth factor. Biochem Biophys Res Commun 284:966–71PubMedCrossRefGoogle Scholar
  30. Riser BL, Denichilo M, Cortes P, Baker C, Grondin JM, Yee J, Narins RG (2000) Regulation of connective tissue growth factor activity in cultured rat mesangial cells and its expression in experimental diabetic glomerulosclerosis. J Am Soc Nephrol 11:25–38PubMedGoogle Scholar
  31. Schleicher E, Nerlich A (1996) The role of hyperglycemia in the development of diabetic complications. Horm Metab Res 28:367–73PubMedCrossRefGoogle Scholar
  32. Schmidt AM, Hori O, Brett J, Yan SD, Wautier JL, Stern D (1994) Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions. Arterioscler Thromb Vasc Biol 14:1521–1528CrossRefGoogle Scholar
  33. Shi-Wen X, Renzoni EA, Kennedy L, Howat S, Chen Y, Pearson JD, Bou-Gharios G, Dashwood MR, du Bois RM, Black CM, Denton CP, Abraham DJ, Leask A (2007) Endogenous endothelin-1 signaling contributes to type I collagen and CCN2 overexpression in fibrotic fibroblasts. Matrix Biol 26:625–32PubMedCrossRefGoogle Scholar
  34. Thomson SE, McLennan SV, Kirwan PD, Heffernan SJ, Hennessy A, Yue DK, Twigg SM (2008) Renal connective tissue growth factor correlates with glomerular basement membrane thickness and prospective albuminuria in a non-human primate model of diabetes: possible predictive marker for incipient diabetic nephropathy. J Diabetes Its Complicat 22:284–94CrossRefGoogle Scholar
  35. Thornalley PJ (1998) Cell activation by glycated proteins. AGE receptors, receptor recognition factors and functional classification of AGEs. Cell Mol Biol 44:1013–1023PubMedGoogle Scholar
  36. Twigg SM (2011) Mastering a mediator: blockade of CCN-2 shows early promise in human diabetic kidney disease. J Cell Commun Signal 4:189–96CrossRefGoogle Scholar
  37. Twigg SM, Chen MM, Joly AH, Chakrapani SD, Tsubaki J, Kim HS, Oh Y, Rosenfeld RG (2001) Advanced glycosylation end products up-regulate connective tissue growth factor (insulin-like growth factor-binding protein-related protein 2) in human fibroblasts: a potential mechanism for expansion of extracellular matrix in diabetes mellitus. Endocrinology 142:1760–9PubMedCrossRefGoogle Scholar
  38. Twigg SM, Cao Z, McLennan SV, Burns WC, Brammar G, Forbes JM, Cooper ME (2002a) Renal connective tissue growth factor induction in experimental diabetes is prevented by aminoguanidine. Endocrinology 143:4907–15CrossRefGoogle Scholar
  39. Twigg SM, Joly AH, Chen MM, Tsubaki J, Kim HS, Hwa V, Oh Y, Rosenfeld RG (2002b) Connective tissue growth factor/IGF-binding protein-related protein-2 is a mediator in the induction of fibronectin by advanced glycosylation end-products in human dermal fibroblasts. Endocrinology 143:1260–9PubMedCrossRefGoogle Scholar
  40. Vlassara H (1992) Receptor-mediated interactions of advanced glycosylation end products with cellular components within diabetic tissues. Diabetes 41:52–56PubMedGoogle Scholar
  41. Vlassara H, Brownlee M, Cerami A (1986) Nonenzymatic glycosylation: role in the pathogenesis of diabetic complications. Clin Chem 32:B37–B41PubMedGoogle Scholar
  42. Wahab NA, Weston BS, Mason RM (2005) Modulation of the TGFbeta/Smad signaling pathway in mesangial cells by CTGF/CCN2. Exp Cell Res 307:305–14PubMedCrossRefGoogle Scholar
  43. Wang JF, Olson ME, Ball DK, Brigstock DR, Hart DA (2003) Recombinant connective tissue growth factor modulates porcine skin fibroblast gene expression. Wound Repair Regen 11:220–9PubMedCrossRefGoogle Scholar
  44. Wang X, McLennan SV, Allen TJ, Tsoutsman T, Semsarian C, Twigg SM (2009) Adverse effects of high glucose and free fatty acid on cardiomyocytes are mediated by connective tissue growth factor. Am J Physiol Cell Physiol 297:C1490–500PubMedCrossRefGoogle Scholar
  45. Zhang C, Zhu Z, Liu J, Yang X, Fu L, Deng A (2007) Role of connective tissue growth factor in extracellular matrix degradation in renal tubular epithelial cells. J Huazhong Univ Sci Technolog Med Sci 27:44–7PubMedCrossRefGoogle Scholar
  46. Ziyadeh FN (1993) The extracellular matrix in diabetic nephropathy. Am J Kidney Dis 22:736–44PubMedGoogle Scholar

Copyright information

© The International CCN Society 2011

Authors and Affiliations

  • Xiaoyu Wang
    • 1
  • Susan V. McLennan
    • 1
    • 2
  • Stephen M. Twigg
    • 1
    • 2
    Email author
  1. 1.Sydney Medical SchoolThe University of SydneySydneyAustralia
  2. 2.Department of EndocrinologyRoyal Prince Alfred HospitalSydneyAustralia

Personalised recommendations