Connective Tissue Growth Factor (CTGF) Expression Modulates Response to High Glucose

Abstract

Connective tissue growth factor (CTGF) is an important mediator of fibrosis; emerging evidence link changes in plasma and urinary CTGF levels to diabetic kidney disease. To further ascertain the role of CTGF in responses to high glucose, we assessed the consequence of 4 months of streptozotocin-induced diabetes in wild type (+/+) and CTGF heterozygous (+/−) mice. Subsequently, we studied the influence of glucose on gene expression and protein in mice embryonic fibroblasts (MEF) cells derived from wildtype and heterozygous mice. At study initiation, plasma glucose, creatinine, triglyceride and cholesterol levels were similar between non-diabetic CTGF+/+ and CTGF+/− mice. In the diabetic state, plasma glucose levels were increased in CTGF+/+ and CTGF+/− mice (28.2 3.3 mmol/L vs 27.0 3.1 mmol/L), plasma triglyceride levels were lower in CTGF+/− mice than in CTGF+/+ (0.7 0.2 mmol/L vs 0.5 0.1 mmol/L, p<0.05), but cholesterol was essentially unchanged in both groups. Plasma creatinine was higher in diabetic CTGF+/+ group (11.7±1.2 vs 7.9±0.6 µmol/L p<0.01), while urinary albumin excretion and mesangial expansion were reduced in diabetic CTGF+/− animals. Cortices from diabetic mice (both CTGF +/+ and CTGF +/−) manifested higher expression of CTGF and thrombospondin 1 (TSP1). Expression of nephrin was reduced in CTGF +/+ animals; this reduction was attenuated in CTGF+/− group. In cultured MEF from CTGF+/+ mice, glucose (25 mM) increased expression of pro-collagens 1, IV and XVIII as well as fibronectin and thrombospondin 1 (TSP1). In contrast, activation of these genes by high glucose was attenuated in CTGF+/− MEF. We conclude that induction of Ctgf mediates expression of extracellular matrix proteins in diabetic kidney. Thus, genetic variability in CTGF expression directly modulates the severity of diabetic nephropathy.

A Novel Role for SIRT-1 in L-Arginine Protection against STZ Induced Myocardial Fibrosis in Rats

“…CTGF, another potent pro-fibrotic protein is reported to mediated tissue and organ fibrosis thus contributing to structural and functional abnormalities in the diabetic heart [53] , [54] . Notably, CTGF expression is increased in type I DM and is accompanied by increased expression of fibronectin and collagen type 1 [55] . Indeed, in the current investigation, STZ, STZ + Stnl or STZ + Stnl+ L-ARG animals displayed increased CGTF expression, which was reversed by L-ARG treatment ( Fig.…”

Diabetes-Induced Reactive Oxygen Species: Mechanism of Their Generation and Role in Renal Injury

“…Therefore, CTGF plays a pivotal role in TGF- β 1-induced ECM production which causes mesangial expansion and increased GBM thickness leading to glomerulosclerosis and interstitial fibrosis, the progressive stage of renal injury [254, 255]. It also induces hypertrophy of mesangial cells through activation of p21 Cip1 and p27 kip1 and causes functional impairment as well as loss of podocytes resulting in diminished regulatory functions of the glomerulus [253, 256].…”

From molecular signatures to predictive biomarkers: modeling disease pathophysiology and drug mechanism of action

“…For seven out of 20 pathways discussed no biomarker or target annotation is identified, and complementary a large number of such features are assigned also outside the pathway landscape presented in Figure 1 . Prominent examples for void biomarker assignment include connective tissue growth factor (CTGF) as factor in fibrosis not being assigned in KEGG, the same being true for uromodulin (UMOD) shown to be associated with progressive disease including genetic polymorphisms (Deshmukh et al, 2013 ; James et al, 2013 ). CTGF is also discussed in the therapeutic context via utilizing a monoclonal antibody-based approach (Adler et al, 2010 ).…”