Fell‐Muir lecture: connective tissue growth factor (CCN2) – a pernicious and pleiotropic player in the development of kidney fibrosis

Abstract

Summary Connective tissue growth factor (CTGF, CCN2) is a member of the CCN family of matricellular proteins. It interacts with many other proteins, including plasma membrane proteins, modulating cell function. It is expressed at low levels in normal adult kidney cells but is increased in kidney diseases, playing important roles in inflammation and in the development of glomerular and interstitial fibrosis in chronic disease. This review reports the evidence for its expression in human and animal models of chronic kidney disease and summarizes data showing that anti‐CTGF therapy can successfully attenuate fibrotic changes in several such models, suggesting that therapies targeting CTGF and events downstream of it in renal cells may be useful for the treatment of human kidney fibrosis. Connective tissue growth factor stimulates the development of fibrosis in the kidney in many ways including activating cells to increase extracellular matrix synthesis, inducing cell cycle arrest and hypertrophy, and prolonging survival of activated cells. The relationship between CTGF and the pro‐fibrotic factor TGFβ is examined and mechanisms by which CTGF promotes signalling by the latter are discussed. No specific cellular receptors for CTGF have been discovered but it interacts with and activates several plasma membrane proteins including low‐density lipoprotein receptor‐related protein (LRP)‐1, LRP‐6, tropomyosin‐related kinase A, integrins and heparan sulphate proteoglycans. Intracellular signalling and downstream events triggered by such interactions are reviewed. Finally, the relationships between CTGF and several anti‐fibrotic factors, such as bone morphogenetic factor‐4 (BMP4), BMP7, hepatocyte growth factor, CCN3 and Oncostatin M, are discussed. These may determine whether injured tissue heals or progresses to fibrosis.

KLF 15 Works as an Early Anti-Fibrotic Transcriptional Regulator in Ang II-Induced Renal Fibrosis via Down-Regulation of CTGF Expression

“…However, CTGF may play an important role in renal fibrosis independent of TGF-β [23]. For example, CTGF can bind to low-density lipoprotein receptor-related protein (LRP1) and epidermal growth factor receptor (EGFR) to activate profibrotic ERK signalling in the kidney [33, 34]. Moreover, many studies have demonstrated that directly decreasing CTGF expression effectively modulates kidney disease [23].…”

Maternal nicotine exposure during gestation and lactation induces kidney injury and fibrosis in rat offspring

“…Current concept suggests that abnormal wound healing of the kidney tissue following recurrent injury is the main cause of the fibrotic response. CTGF is a fibroblast mitogen and promoter of collagen deposition that acts downstream of transforming growth factor-β1, particularly regarding its profibrotic effects (18,33,34). In this study, we found that nicotine exposure during gestation and lactation increased total collagen contents Figure 5.…”

“…CTGF plays a crucial role in kidney pathogenesis, which include migration, hypertrophy, and fibronectin production in mesangial cells, epithelialmesenchymal transition and fibronectin production of tubular epithelial cells, and collagen production by renal interstitial fibroblasts (14)(15)(16)(17)(18). Nicotine has been reported to increase CTGF mRNA and protein expression in proximal tubular epithelial cells and human gingival fibroblasts (19,20).…”

Matricellular Proteins and Organ Fibrosis

“…CCN2 was shown to exert its functions through direct activation of cells to produce ECM, induction of cell cycle arrest or hypertrophy, and conversion of resident cells to activated myofibroblasts. CCN2 acts downstream the pro-fibrotic cytokine TGFβ, but it has also been shown to activate or co-activate TGFβ through binding to cell-surface receptors like tropomyosin-related kinase A (TrkA) and activation of downstream signaling which prevents the expression of inhibitory Smad7 (6,7). More recent findings verified the pro-fibrotic role of CCN2 in the mdx mouse model of muscular dystrophy, since hemizygous mice or mice treated with an anti-CTGF monoclonal antibody showed improved muscle strength, reduced apoptotic damage and fibrosis (8).…”