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Targeting CTGF, EGF and PDGF pathways to prevent progression of kidney disease

  • Review Article
  • Published:

From Nature Reviews Nephrology

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Key Points

  • During progression of chronic kidney disease, the sustained release of proinflammatory and profibrotic cytokines and growth factors leads to an excessive accumulation of extracellular matrix resulting in kidney fibrosis

  • Transforming growth factor β (TGF-β) is the main driving force in fibrotic development, but connective tissue growth factor (CTGF), epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) also induce fibrosis

  • CTGF, EGF and PDGF and their receptors constitute alternative therapeutic targets to TGF-β, especially if concerns regarding the risks associated with blocking the beneficial actions of TGF-β are valid

  • Considering the substantial interaction between growth factors, it seems that targeting multiple growth factors might represent the best strategy for treatment of kidney fibrosis

Abstract

Chronic kidney disease (CKD) is a major health and economic burden with a rising incidence. During progression of CKD, the sustained release of proinflammatory and profibrotic cytokines and growth factors leads to an excessive accumulation of extracellular matrix. Transforming growth factor β (TGF-β) and angiotensin II are considered to be the two main driving forces in fibrotic development. Blockade of the renin–angiotensin–aldosterone system has become the mainstay therapy for preservation of kidney function, but this treatment is not sufficient to prevent progression of fibrosis and CKD. Several factors that induce fibrosis have been identified, not only by TGF-β-dependent mechanisms, but also by TGF-β-independent mechanisms. Among these factors are the (partially) TGF-β-independent profibrotic pathways involving connective tissue growth factor, epidermal growth factor and platelet-derived growth factor and their receptors. In this Review, we discuss the specific roles of these pathways, their interactions and preclinical evidence supporting their qualification as additional targets for novel antifibrotic therapies.

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Figure 1: Interactions between CTGF, EGF, PDGF and the profibrotic TGF-β pathway.

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  1. Department of Pathology, H04.312, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, Netherlands

    Helena M. Kok, Lucas L. Falke, Roel Goldschmeding & Tri Q. Nguyen

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  2. Lucas L. Falke
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All authors researched the data for the article, contributed substantially to discussion of the content and wrote the article. R.G. and T.Q.N. reviewed and edited the manuscript before submission. H.M.K. and L.L.F contributed equally.

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Correspondence to Roel Goldschmeding.

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R.G. has received research support from FibroGen. The other authors declare no competing interests.

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Kok, H., Falke, L., Goldschmeding, R. et al. Targeting CTGF, EGF and PDGF pathways to prevent progression of kidney disease. Nat Rev Nephrol 10, 700–711 (2014). https://doi.org/10.1038/nrneph.2014.184

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