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Central Role of CTGF

CTGF is being recognized as a central mediator in the pathophysiology of diabetic kidney disease (DKD).^1-3  This increased recognition stems from clinical and nonclinical data demonstrating that:

• Increasing CTGF levels correlate with disease progression: An analysis of the landmark Diabetes Complications and Control Trial (DCCT) / Epidemiology of Diabetes Interventions and Complications (EDIC) study showed that significantly higher levels of plasma CTGF are apparent in advanced kidney disease as measured by albumin excretion rate (AER).⁴  A separate study showed that urine levels of CTGF increased exponentially as renal disease progresses from normalbuminuria, to micro- and macroalbuminuria and ultimately to ESRD.⁵
• CTGF is up-regulated by key drivers of DKD: Nonclinical research, including in vitro studies of human kidney cells, has shown that CTGF is significantly up-regulated by components of key pathways driving the progression of DKD including: hyperglycemia,^6-10  hypertension,^11-13  and the renin-angiotensinaldosterone system (RAAS) (angiotensin-II, endothelin-I, aldosterone);^14-17  stimulators of blood vessel growth and function (thrombin, VEGF, TGF-β);^18-21  stimulators of cell growth (EGF, bFGF);²²  and the kallikrein-kinin system (KKS).²³  View Illustration
• Blocking CTGF attenuates key pathologies induced by drivers of DKD: Nonclinical studies have demonstrated that blocking CTGF attenuates advanced glycation endpproducts (AGE)- and RAAS-induced renal pathologies including: tubular cell hypertrophy,^10,16,24  epithelial mesenchymal transition,²⁵  and fibronectin synthesis.^14,26  Other nonclinical studies show that protein kindase C (PKC)-induced pathologies may be mediated by CTGF, including mesangial cell migration²⁷ and fibrosis.²⁸  PKC has also been shown to mediate angiotensin-II-induced expression of CTGF in diabetic states.¹⁷  CTGF and collagen expression were associated with KKS-induced pathology in a nonclinical study examining mechanisms through which bradykinin promotes glomerular injury in diabetes.²³
• Blocking CTGF attenuates proteinuria: VEGF and AGE have been implicated as key factors in promoting early pathologies associated with DKD, such as hyperfiltration and the onset of proteinuria,^29,30  and recent nonclinical studies suggest a role for CTGF in mediating these same effects. In an experimental model of early-stage DKD, anti-CTGF therapy normalized kidney hyperfiltration and reduced kidney hypertrophy, excess urine production, proteinuria, and glomerular membrane thickening.³¹  Other studies have shown that CTGF is highly expressed in cell types involved in the development of proteinuria including vascular endothelial cells³² and podocytes³³ and over-expression of CTGF in a model of DKD worsened proteinuria.³⁸
• Blocking CTGF prevents renal fibrosis in vitro and in animal models: The prominent role that CTGF plays in renal fibrosis has been clearly demonstrated by multiple studies in which blocking the synthesis of or directly inhibiting CTGF prevented key steps of renal fibrosis including transdifferentiation of normal human renal tubular epithelial cells to scar-producing myofibroblasts,^34-35  production of key proteins that compose scar,^3,6,13,33  and development of kidney fibrosis.^11,36,37

References

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2. van Nieuwenhoven, F.A., et al., Imbalance of growth factor signalling in diabetic kidney disease: is connective tissue growth factor (CTGF, CCN2) the perfect intervention point? Nephrol Dial Transplant, 2005. 20(1): p. 6-10.
3. Wahab, N.A., et al., Role of connective tissue growth factor in the pathogenesis of diabetic nephropathy. Biochem J, 2001. 359(Pt 1): p. 77-87.
4. Jaffa AA, et al. Connective tissue growth factor and susceptibility to renal and vascular disease risk in type 1 diabetes. J Clin Endocrinol Metab. 2008 May;93(5):1893-900.
5. Ito Y., et al., Human urinary CTGF (CCN2) as a predictor of progression of chronic renal diseases (Abst). American Society of Nephrology Renal Week 2003: Abstract F-PO412. (Abstract).
6. Lam, S., et al., Connective tissue growth factor and igf-I are produced by human renal fibroblasts and cooperate in the induction of collagen production by high glucose. Diabetes, 2003. 52(12): p. 2975-83.
7. Murphy, M., et al., 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, 1999. 274(9): p. 5830-4.
8. Twigg, S.M., et al., 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, 2002. 143(4): p. 1260-9.
9. Zhou, G., C. Li, and L. Cai, Advanced glycation end-products induce connective tissue growth factormediated renal fibrosis predominantly through transforming growth factor beta-independent pathway. Am J Pathol, 2004. 165(6): p. 2033-43.
10. Burns W.C., 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. 2006 Sep;17(9):2484-94.
11. Hishikawa, K., B.S. Oemar, and T. Nakaki, Static pressure regulates connective tissue growth factor expression in human mesangial cells. J Biol Chem, 2001. 276(20): p. 16797-803.
12. Chaqour, B., R. Yang, and Q. Sha, Mechanical Stretch Modulates the Promoter Activity of the Profibrotic Factor CCN2 through Increased Actin Polymerization and NF-{kappa}B Activation. J Biol Chem, 2006. 281(29): p. 20608-22.
13. Graness, A., I. Cicha, and M. Goppelt-Struebe, Contribution of Src-FAK signaling to the induction of connective tissue growth factor in renal fibroblasts. Kidney Int, 2006. 69(8): p. 1341-9.
14. Ruperez, M., et al., Angiotensin II increases connective tissue growth factor in the kidney. Am J Pathol, 2003. 163(5): p. 1937-47.
15. Xu, S.W., et al., Endothelin-1 induces expression of matrix-associated genes in lung fibroblasts through MEK/ERK. J Biol Chem, 2004. 279(22): p. 23098-103.
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17. He, Z., et al., Differential regulation of angiotensin II-induced expression of connective tissue growth factor by protein kinase C isoforms in the myocardium. J Biol Chem, 2005. 280(16): p. 15719-26.
18. Chambers, R.C., et al., Thrombin is a potent inducer of connective tissue growth factor production via proteolytic activation of protease-activated receptor-1. J Biol Chem, 2000. 275(45): p. 35584-91.
19. He, S., et al., A role for connective tissue growth factor in the pathogenesis of choroidal neovascularization. Arch Ophthalmol, 2003. 121(9): p. 1283-8.
20. Igarashi, A., et al., Regulation of connective tissue growth factor gene expression in human skin fibroblasts and during wound repair. Mol Biol Cell, 1993. 4(6): p. 637-45.
21. Suzuma, K., et al., Vascular endothelial growth factor induces expression of connective tissue growth factor via KDR, Flt1, and phosphatidylinositol 3-kinase-akt-dependent pathways in retinal vascular cells. J Biol Chem, 2000. 275(52): p. 40725-31.
22. Wunderlich, K., et al., Regulation of connective tissue growth factor gene expression in retinal vascular endothelial cells by angiogenic growth factors. Graefes Arch Clin Exp Ophthalmol, 2000. 238(11): p. 910-5.
23. Tan, Y., et al., Mechanisms through which bradykinin promotes glomerular injury in diabetes. Am J Physiol Renal Physiol, 2005. 288(3): p. F483-92.
24. Liu, BC, et al., Connective tissue growth factor-mediated angiotensin II-induced hypertrophy of proximal tubular cells. Nephron Exp Nephrol. 2006;103(1):e16-26.
25. Chen, L, et al., Influence of connective tissue growth factor antisense oligonucleotide on angiotensin II-induced epithelial mesenchymal transition in HK2 cells. Acta Pharmacol Sin. 2006 Aug;27(8):1029-36.
26. Ruperez M., Connective tissue growth factor is a mediator of angiotensin II-induced fibrosis. Circulation. 2003 Sep 23;108(12):1499-505.
27. Crean, J.K., et al., Connective tissue growth factor [CTGF]/CCN2 stimulates mesangial cell migration through integrated dissolution of focal adhesion complexes and activation of cell polarization. FASEB J. 2004 Oct;18(13):1541-3.
28. Way, K.J., et al. Expression of connective tissue growth factor is increased in injured myocardium associated with protein kinase C beta2 activation and diabetes. Diabetes. 2002 Sep;51(9):2709-18.
29. Flyvbjerg, A., et al., Amelioration of long-term renal changes in obese type 2 diabetic mice by a neutralizing vascular endothelial growth factor antibody. Diabetes. 2002 Oct;51(10):3090-4.
30. Flyvbjerg, A., et al., Long-term renal effects of a neutralizing RAGE antibody in obese type 2 diabetic mice Diabetes. 2004 Jan;53(1):166-72.
31. Flyvbjerg, A., et al., Long-Term Renal Effects of a Neutralizing Connective Tissue Growth Factor (CTGF)-Antibody in Obese Type 2 Diabetic Mice. J Am Soc Nephrol. 2004. 15:261A.
32. Suzuma, K., et al., Vascular endothelial growth factor induces expression of connective tissue growth factor via KDR, Flt1, and phosphatidylinositol 3-kinase-akt-dependent pathways in retinal vascular cells. J Biol Chem. 2000 Dec 29;275(52):40725-31.
33. Roestenberg, P., et al., Temporal expression profile and distribution pattern indicate a role of connective tissue growth factor (CTGF/CCN-2) in diabetic nephropathy in mice. Am J Physiol Renal Physiol. 2006 Jun;290(6):F1344-54.
34. Zhang, C., et al., Connective tissue growth factor regulates the key events in tubular epithelial to myofibroblast transition in vitro. Cell Biol Int, 2004. 28(12): p. 863-73.
35. Zhang, C., et al., Role of connective tissue growth factor in renal tubular epithelial-myofibroblast transdifferentiation and extracellular matrix accumulation in vitro. Life Sci, 2004. 75(3): p. 367-79.
36. Yokoi, H., et al., Reduction in connective tissue growth factor by antisense treatment ameliorates renal tubulointerstitial fibrosis. J Am Soc Nephrol, 2004. 15(6): p. 1430-40.
37. Okada, H., et al., Dexamethasone induces connective tissue growth factor expression in renal tubular epithelial cells in a mouse strain-specific manner. Am J Pathol, 2006. 168(3): p. 737-47
38. Yokoi H, et al. Overexpression of connective tissue growth factor in podocytes worsens diabetic nephropathy in mice. Kidney Int. 2008 Feb;73(4):446-55.