Plasma Connective Tissue Growth Factor Levels Research Articles

The association of plasma connective tissue growth factor levels with left ventricular diastolic dysfunction in patients with overt hyperthyroidism.

Left ventricular (LV) diastolic dysfunction is an independent predictor of future cardiovascular events. Early detection of patients with LV diastolic dysfunction can improve clinical outcomes through active management. However, the assessment of diastolic function is very complicated, and there are currently lack of effective biomarkers to assess the risk of LV diastolic dysfunction. Connective tissue growth factor (CTGF) plays a significant role in cardiac remodeling and dysfunction. We aimed to investigate the associations between plasma CTGF level and the risk of LV diastolic dysfunction in this study and judge its effectiveness in diagnosing LV diastolic dysfunction. A total of 169 patients with overt hyperthyroidism were included. LV diastolic function was evaluated and the subjects were divided into normal LV diastolic function group and LV diastolic dysfunction group. Routine clinical medical data, biochemical data, thyroid related parameters and echocardiographic parameters were recorded for analysis. Compared with normal LV diastolic function group, the LV diastolic dysfunction group had higher age and BMI, as well as lower heart rate, lower serum albumin, lower eGFR, higher serum TgAb and BNP level, and the incidences of hypertension were also higher (all P <0.05). Circulating plasma CTGF levels in the LV diastolic dysfunction group were significantly higher (normal LV diastolic function group: 7.026 [5.567-8.895], LV diastolic dysfunction group: 8.290 [7.054-9.225] ng/ml, median [(Interquartile range)], P = 0.004); Compared with the lowest quartile group, the crude odds ratios (OR) of LV diastolic dysfunction in the second, third, and fourth quartile group were 3.207, 5.032 and 4.554, respectively (all P<0.05). After adjustment for the potentially confounding variables, the adjusted OR values of the third and fourth quartile group had no obvious change. The results of ROC showed that the plasma CTGF had the largest area under the ROC curve, and the value was 0.659 (P = 0.005). The level of circulating plasma CTGF in the LV diastolic dysfunction group was significantly increased. Plasma CTGF level is an independent risk factor for LV diastolic dysfunction. Compared with serum BNP level, the plasma CTGF level may have auxiliary diagnostic value for LV diastolic dysfunction in hyperthyroid patients.

Role of Plasma Connective Tissue Growth Factor Levels in Assessment of Pulmonary Arterial Hypertension in Children with Congenital Heart Disease

Abstract Background: To investigate plasma Connective Tissue Growth Factor (CTGF) levels in Pulmonary Arterial Hyper-tension (PAH) associated with Congenital Heart Disease (PAH-CHD) in children and the relationships of CTGF with hemodynamic parameters. Plasma CTGF levels were calculated in 30 children with PAH-CHD and 30 health volunteers, using the subtraction method. Aim of Study: To assess plasma Connective Tissue Growth Factor (CTGF) levels in children with CHD and study its role in assessment of PAH that can be promising diagnostic and prognostic biomarkers for PAH in children with CHD. Patients and Methods: Our study was conducted in Pedi-atric Cardiology Clinic and Cardiology Catheter Laboratory of Ain Shams University Pediatric Hospital, in the period from Jan. 2019 to May 2020, including 30 patient and 30 healthy controls of matched age and sex. Results: The patients with PAH, 17 were acyanotic and 13 were cyanotic. The health control group and patient groups did not differ significantly in terms of age, gender and BSA (p>0.05). Height, weight and BMI were significantly lower in PAH-CHD group compared with the HCG (p 0.05). In addition, CTGF levels were higher in PAH-CHD group than health control group. Depicts that, PAH-CHD group had higher PASP, PADP, RVSP, mPAP, Qp, Rp and Rp/Rs (p < 0.01). Conclusion: Plasma CTGF levels could be a promising diagnostic biomarker for PAH-CHD in children.

Association of Plasma Connective Tissue Growth Factor Levels with Hyperthyroid Heart Disease

Hyperthyroid heart disease (HHD) is one of the most severe complications of overt hyperthyroidism and increases the risk of mortality in affected patients. Early identification of patients at a higher risk of developing HHD can improve clinical outcomes through active surveillance and management. Connective tissue growth factor (CTGF), a secreted extracellular protein, plays a significant role in cardiac remodeling and dysfunction. We aimed to investigate the association between plasma CTGF level and the risk of HHD in this study. A total of 142 overt hyperthyroid patients without HHD and 99 patients with HHD were included. The plasma CTGF levels were measured using ELISA kits. Routine clinical medical data and echocardiography parameters were recorded for analysis. The plasma CTGF level was significantly higher in patients with HHD than in those without HHD (P=0.002). The plasma CTGF level was positively correlated with free triiodothyronin, tryrotropin receptor antibody, troponin I and lactate dehydrogenase levels and the left atrium diameters, right atrium diameters, and right ventricular end-diastolic diameters (all P<0.05). Logistic regression analysis showed that quartiles 3 and 4 of plasma CTGF levels were significantly associated with the increased risk of HHD (crude OR: 2.529; 95% CI: 1.188-5.387). However, after adjustment for the potentially confounding variables, quartile 4 alone was significantly associated with the higher risk of HHD relative to quartile 1. Hyperthyroid patients with HHD display higher plasma CTGF levels. Furthermore, CTGF is an independent risk factor for HHD. Therefore, the plasma CTGF level may be a potential biomarker for the risk of HHD.

Circulating Connective Tissue Growth Factor Is Associated with Diastolic Dysfunction in Patients with Diastolic Heart Failure

Background: Connective tissue growth factor (CTGF) and transforming growth factor β1 (TGF-β1) are emerging biomarkers for tissue fibrosis. The aim of this study was to investigate the association between circulating CTGF, TGF-β1 levels and cardiac diastolic dysfunction in patients with diastolic heart failure (DHF). Methods: Admitted subjects were screened for heart failure and those with left ventricular (LV) ejection fraction <45% were excluded. Diastolic dysfunction was defined as functional abnormalities that exist during LV relaxation and filling by echocardiographic criteria. Totally 114 patients with DHF and 72 controls were enrolled. Plasma levels of CTGF, TGF-β1, and B-type natriuretic peptide (BNP) were determined. Results: The plasma CTGF and TGF-β1 levels increased significantly in patients with DHF. Circulating CTGF and TGF-β1 levels were correlated with echocardiographic parameter E/e’ and diastolic dysfunction grading in DHF patients. In multivariate logistic analysis, CTGF was significantly associated with diastolic dysfunction (odds ratio: 1.027, p < 0.001). Plasma CTGF (AUC: 0.770 ± 0.036, p < 0.001) and CTGF/BNP (AUC: 0.839 ± 0.036, p < 0.001) showed good predictive power to the diagnosis of DHF. Conclusions: This finding suggested CTGF could be involved in the pathophysiology of diastolic heart failure and CTGF/BNP might have auxiliary diagnostic value on diastolic heart failure.

Elevated Plasma Connective Tissue Growth Factor Levels in Children with Pulmonary Arterial Hypertension Associated with Congenital Heart Disease.

We aimed to investigate plasma connective tissue growth factor (CTGF) levels in pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD) (PAH-CHD) in children and the relationships of CTGF with hemodynamic parameters. Plasma CTGF levels were calculated in 30 children with CHD, 30 children with PAH-CHD and 25 health volunteers, using the subtraction method. Cardiac catheterization was performed to measure clinical hemodynamic parameters. Plasma CTGF levels were significantly higher in PAH-CHD than in those with CHD and health volunteers (p < 0.01). In cyanotic PAH-CHD, plasma CTGF levels were significantly elevated compared with acyanotic PAH-CHD in the same group (p < 0.05). Plasma CTGF levels showed positive correlation with B-type natriuretic peptide (BNP) in PAH-CHD (r = 0.475, p < 0.01), while oxygen saturation was inversely related to plasma CTGF levels (r = -0.436, p < 0.05). There was no correlation between CTGF and hemodynamic parameters. Even though the addition of CTGF to BNP did not significantly increase area under curve for diagnosis of PAH-CHD compared with BNP alone (p > 0.05), it revealed a moderately better specificity, positive predictive value and positive likelihood ratio than BNP alone. Plasma CTGF levels could be a promising diagnostic biomarker for PAH-CHD in children.

Plasma connective tissue growth factor levels as potential biomarkers of airway obstruction in patients with asthma

BackgroundBronchial asthma is a chronic inflammatory disorder characterized by airway hyperresponsiveness and airflow limitation. Connective tissue growth factor (CTGF), one of the key profibrotic factors associated with transforming growth factor β, may be related to airway remodeling in asthma. However, no data are available on the association between plasma CTGF levels and clinical and physiologic parameters in patients with asthma. Recently, we developed a novel subtraction method for determination of plasma CTGF levels. ObjectiveTo investigate the utility of plasma CTGF level as a surrogate biomarker in asthma. MethodsPlasma CTGF levels were measured in 67 patients with stable asthma and 81 healthy volunteers, using the subtraction method. We evaluated correlations between plasma CTGF levels and clinical and physiologic parameters in patients with asthma. ResultsPlasma CTGF levels were higher in patients with asthma than in healthy volunteers. Asthmatic patients with a percentage of predicted forced expiratory volume in 1 second (FEV1) less than 80% had significantly higher levels of plasma CTGF than those with a percentage of predicted FEV1 of 80% or more. In patients with asthma, plasma CTGF levels had significantly negative correlations with forced vital capacity (FVC), FEV1, percentage of predicted FEV1, FEV1/FVC ratio, forced expiratory flow at 50% of the FVC (FEF50%), percentage of predicted FEF50%, forced expiratory flow at 75% of the FVC (FEF75%), and percentage of predicted FEF75%, parameters that reflect the degree of airway obstruction. Plasma CTGF levels were negatively correlated with Asthma Control Test scores, a patient-based index of clinical control of asthma. ConclusionPlasma CTGF may be a potential biomarker for stable asthma when evaluating the degree of persistent airway obstruction. Trial Registrationumin.ac.jp/ctr Identifier: UMIN000013081

Connective tissue growth factor and cardiac diastolic dysfunction: human data from the Taiwan Diastolic Heart Failure Registry and molecular basis by cellular and animal models

Connective tissue growth factor (CTGF) is an emerging marker for tissue fibrosis. We investigated the association between CTGF and cardiac diastolic function using cellular and animal models and clinical human data. A total of 125 patients with a diagnosis of diastolic heart failure (DHF) were recruited from 1283 patients of the Taiwan Diastolic Heart Failure Registry. The severity of DHF was determined by tissue Doppler imaging (E/e'). Cardiac magnetic resonance imaging (CMRI) was used to evaluate myocardial fibrosis in some of the patients (n = 25). Stretch of cardiomyocytes on a flexible membrane base serves as a cellular phenotype of cardiac diastolic dysfunction (DD). A canine model of DD was induced by aortic banding. A significant correlation was found between plasma CTGF and E/e' in DHF patients. The severity of cardiac fibrosis evaluated by CMRI also correlated with CTGF. In the cell model, stretch increased secretion of CTGF from cardiomyocytes. In the canine model, myocardial tissue CTGF expression and fibrosis significantly increased after 2 weeks of aortic banding. Notably, the expression of CTGF paralleled the severity of LV DD (r = 0.40, P < 0.001 for E/e') and haemodynamic changes (r = 0.80, P < 0.001). After adjusting for confounding factors, CTGF levels still correlated with diastolic parameters in both human and canine models (human plasma CTGF, P < 0.001; canine tissue CTGF, P = 0.04). Plasma CTGF level correlated with the severity of DD and tissue fibrosis in DHF patients. The mechanism may be through myocardial stretch. Our study indicated that CTGF may serve as an early marker for DHF.

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

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.

FG-3019, a human monoclonal antibody to CTGF, with gemcitabine/erlotinib in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma.

213 Background: Connective tissue growth factor (CTGF) is overexpressed in PDAC and facilitates local desmoplasia, tumor survival and metastasis. FG-3019 is a CTGF-specific monoclonal antibody that decreases tumor growth and metastases and prolongs survival in orthotopic and KPC mouse models. This study evaluates safety and efficacy of FG-3019 with gemcitabine/erlotinib in patients with PDAC. Methods: In a nongoing open-label, dose-escalation study, FG-3019 was used in combination with gemcitabine and erlotinib in patients with previously untreated, measurable, locally advanced or metastatic PDAC. Cohorts 1−6 received FG-3019 Q2W at 3, 10, 15, 25, 35 or 45 mg/kg. Cohort 7 received 35 mg/kg on Day 1 and then 17.5 mg/kg QW. Cohort 8 received 45 mg/kg on Day 1 and then 22.5 mg/kg QW. Results: 75 patients were enrolled at 7 centers. Baseline data: Stage III= 15, Stage IV=60; ECOG=0 (n=32), ECOG=1 (N=43). No SAEs or DLTs related to FG-3019 occurred at any dose. In per protocol population (n=68) median PFS and OS were 4.3 and 9.4 months respectively. Baseline plasma CTGF levels correlated inversely with PFS and OS (p=0.0029) (ITT population). Median FG-3019 Cmax and Cmin increased linearly with dose. Because of considerable overlap between subjects across cohorts, outcomes are correlated with drug exposure. OS, but not PFS, correlated with exposure after the first FG-3019 dose (Day 1 Cmax, p=0.009; Day 15 Cmin, p=0.005; ITT population). 47% of evaluable subjects had &gt;50% decrease in CA19.9.The magnitude of reduction correlated with Day 1 Cmax (p=0.04) and inversely with baseline plasma CTGF (p=0.01). As FG-3019 accumulated over time, minimum FG-3019 exposure (Cmin) of 150 ug/mL on Day 43 appeared to be a threshold. Median OS was 7.7 and &gt;8.6 months for subjects &lt; (n=15) or ≥ (n=43) 150 ug/mL respectively on Day 43 (p=0.0034). Day 43 Cmin &lt; 150, none alive at 12 months: Day 43 Cmin &gt;150, 8 alive at 12 months, 17 alive 6.7-12 months. Conclusions: FG-3019 combined with gemcitabine/erlotonib is well tolerated. Interim results in this open-label study suggest OS improves with increasing exposure to FG-3019. Clinical trial information: NCT01181245.

Abstract 19068: Connective Tissue Growth Factor in Human Diastolic Heart Failure from the Taiwan Diastolic Heart Failure Registry and a Canine Model of Diastolic Dysfunction

BACKGROUND: Diastolic heart failure (DHF) is characterized by myocardial interstitial fibrosis and left ventricular hypertrophy. The study investigated the association between connective tissue growth factor (CTGF) and DHF from animal model to clinical indices. METHODS: The participants of current study were enrolled from the Taiwan Diastolic Heart Failure Registry (TDHFR). 1284 patients were screened and a total of 125 patients with a diagnosis of DHF confirmed by echocardiography were recruited. The severity of DHF was decided according to tissue doppler imaging (E/e’). Soluble plasma levels of CTGF were measured in all subjects and the associations with diastolic function parameters were calculated. Canine model of DHF was induced by aortic banding. Hemodynamic and echocardiographic data were obtained before and after pressure loading (at baseline and after 2 weeks). Myocardium tissues were collected, and western blotting was used to detect the protein expression of CTGF for each dog. The correlation between CTGF, the severity of diastolic dysfunction and hemodynamic changes was then calculated. RESULTS: Patients with severe DHF presented significantly higher plasma CTGF levels than the controls. Significant correlation were found for plasma CTGF and E/e’ (r = 0.80, p&lt;0.001) in advanced DHF patients (E/e’ &gt;15). After 2 weeks in canine models, the protein expression of CTGF from LV myocardial tissue was significantly increased (p&lt;0.01) compared with the controls (shame dogs). Moreover, the expression of CTGF paralleled the severity of LV diastolic dysfunction parameters (r= 0.70, p= 0.03 for E/e’) and hemodynamic changes (r= 0.75, p= 0.02). After adjusting the possible confounding factors for diastolic dysfunction, CTGF levels were associated with diastolic parameters both in human and canine models (Plasma CTGF, B=0.064, p&lt;0.001; tissue CTGF, B= 9.87, p = 0.05). CONCLUSIONS: Both Plasma and myocardium CTGF levels had significant correlations to the severity of DHF. Our study offered the evidence to apply novel therapies for DHF patients aim to down-regulate the overexpression of CTGF.

Plasma and synovial fluid connective tissue growth factor levels are correlated with disease severity in patients with knee osteoarthritis

Background: Connective tissue growth factor (CTGF) has been implicated in development of osteoarthritis (OA).Objective: To determine the correlation between plasma and synovial fluid CTGF levels and the severity in knee osteoarthritis patients.Methods: A total of 100 subjects were recruited into this study (75 OA patients and 25 controls). CTGF concentrations in plasma and synovial fluid were analyzed by enzyme-linked immunosorbent assay.Results: Plasma and synovial fluid CTGF concentrations were correlated with radiographic severity. There was a positive correlation between plasma and synovial fluid CTGF levels.Conclusion: CTGF could be useful for monitoring the severity and progression of OA.

Clinical significance of inflammatory and fibrogenic cytokines in diabetic nephropathy

To study the role of inflammatory chemokine; monocyte chemoattractant protein-1 (MCP-1), and fibrogenic markers [transforming growth factor beta-1 (TGF-β(1)), connective tissue growth factor (CTGF) and fibronectin (FN)] in diabetic nephropathy (DN). This study included 17 control and 65 type 2 diabetic subjects (18 normoalbuminuric, 22 microalbuminuric and 25 macroalbuminuric). Demographic characteristics, diabetic index and kidney function tests were monitored. Serum TGF-β(1), plasma CTGF, MCP-1 and FN levels were assayed. Microalbuminuric and macroalbuminuric subjects showed a significant elevation in TGF-β(1), CTGF, MCP-1 and FN levels as compared with control and normoalbuminuric subjects. There was positive correlation between these markers and fasting plasma glucose, albumin excretion rate and with each other. This study revealed the importance of these markers in DN pathogenesis which is powered by their association and thus the possibility of their use as biochemical markers in DN was suggested.

Effect of GFR on Plasma N-Terminal Connective Tissue Growth Factor (CTGF) Concentrations

Connective tissue growth factor (CTGF) has a key role in the pathogenesis of renal and cardiac fibrosis. Its amino-terminal fragment (N-CTGF), the predominant form of CTGF detected in plasma, has a molecular weight in the middle molecular range (18 kDa). However, it is unknown whether N-CTGF is a uremic retention solute that accumulates in chronic kidney disease (CKD) due to decreased renal clearance and whether it can be removed by hemodiafiltration. 4 observational studies in patients and 2 pharmacokinetic studies in rodents. 4 single-center studies. First study (cross-sectional): 88 patients with CKD not receiving kidney replacement therapy. Second study (cross-sectional): 23 patients with end-stage kidney disease undergoing low-flux hemodialysis. Third study: 9 kidney transplant recipients before and 6 months after transplant. Fourth study: 11 low-flux hemodialysis patients and 12 hemodiafiltration patients before and after one dialysis session. First, second, and third study: (residual) glomerular filtration rate (GFR). Fourth study: dialysis modality. Plasma (N-)CTGF concentrations, measured by enzyme-linked immunosorbent assay. In patients with CKD, we observed an independent association between plasma CTGF level and estimated GFR (β = -0.72; P < 0.001). In patients with end-stage kidney disease, plasma CTGF level correlated independently with residual kidney function (β = -0.55; P = 0.046). Successful kidney transplant resulted in a decrease in plasma CTGF level (P = 0.008) proportional to the increase in estimated GFR. Plasma CTGF was not removed by low-flux hemodialysis, whereas it was decreased by 68% by a single hemodiafiltration session (P < 0.001). Pharmacokinetic studies in nonuremic rodents confirmed that renal clearance is the major elimination route of N-CTGF. Observational studies with limited number of patients. Fourth study: nonrandomized, evaluation of the effect of one session; randomized longitudinal study is warranted. Plasma (N-)CTGF is eliminated predominantly by the kidney, accumulates in CKD, and is decreased substantially by a single hemodiafiltration session.

Relation Between Connective Tissue Growth Factor and Cardiac Sympathetic Nerve Activity in Heart Failure in DCM Patients

Cardiac fibrosis is an important process of myocardial remodeling. Connective tissue growth factor (CTGF) is a cytokine that plays a key role in the occurrence of progressive fibrosis and excessive scarring. CTGF levels are increased in the failing heart. In addition, sympathetic nerve activity is enhanced in the failing heart, and exacerbates heart failure. To clarify the relation between cardiac sympathetic nerve activity and CTGF, we studied 35 (M/F = 28/7 patients) aged 57 ± 15 years with dilated cardiomyopathy (DCM). Cardiac sympathetic nerve activity was estimated from the total defect score (TDS) and from the H/M ratio and washout rate (WR) on I-123-MIBG imaging. Cardiac symptoms (NYHA class), exercise capacity (specific activity scale: SAS), brain natriuretic peptide (BNP), hemodynamics, and CTGF were assessed. There was a significant correlation between the CTGF and WR on I-123-MIBG (r = 0.45, P = 0.008). Also, a higher plasma CTGF level was associated with a lower SAS score (r = 0.51, P = 0.002), but not the TDS, H/M ratio, or BNP concentration. Moreover, a higher NYHA class and pulmonary artery wedge pressure were associated with a higher plasma CTGF level. The plasma CTGF level can be strongly related with cardiac sympathetic nerve activity in heart failure in DCM patients.

Subtraction method for determination of N-terminal connective tissue growth factor

Connective tissue growth factor (CTGF) may be a potential marker of fibrosis. However, platelet-derived CTGF may be released into the plasma by platelet activation during or after blood collection, thereby interfering with accurate determination of the true plasma CTGF level. Plasma CTGF exists as the N-terminal CTGF fragment (N-fragment), composed of modules 1 and 2, whereas platelet CTGF exists as full-length CTGF (full-length), composed of modules 1-4. We perceived the need to develop a method for distinguishing between the N-fragment and full-length CTGF levels, so that the true plasma and serum CTGF (N-fragment) levels could be accurately determined. Full-length levels were determined by a sandwich enzyme-linked immunosorbent assay (ELISA) using two monoclonal antibodies recognizing modules 1 and 4, respectively (M1/4 ELISA). Total CTGF (full-length CTGF plus N-terminal CTGF) levels were determined by a sandwich ELISA using two monoclonal antibodies recognizing modules 1 and 2, respectively (M1/2 ELISA). N-terminal CTGF levels were determined by subtracting the full-length levels from the total CTGF levels. Both the M1/2 and M1/4 ELISAs showed good analytical performance. When the CTGF levels of plasma and serum collected simultaneously from the same subject were compared, the N-fragment levels determined by the subtraction method were the same, in spite of the fact that full-length CTGF was present in the sample. N-fragment levels in plasma and serum can be accurately determined by this subtraction method, even if full-length CTGF in platelets is released during or after blood collection.

Temporal expression profile and distribution pattern indicate a role of connective tissue growth factor (CTGF/CCN-2) in diabetic nephropathy in mice

Connective tissue growth factor (CTGF) is overexpressed in diabetic nephropathy (DN) and has therefore been implicated in its pathogenesis. The objective of the present study was to determine the tissue distribution of increased CTGF expression and the relationship of plasma, urinary, and renal CTGF levels to the development and severity of DN. We studied the relationship between CTGF and renal pathology in streptozotocin (STZ)-induced diabetes in C57BL/6J mice. Diabetic and age-matched control mice were killed after 1, 2, 4, and 9 wk of diabetes. In addition, key parameters of diabetes and DN were analyzed in 10-mo-old diabetic ob/ob mice and their ob/+ littermates. STZ-induced diabetic mice showed a significantly increased urinary albumin excretion after 1 wk and increased mesangial matrix score after 2 wk. Increased renal fibronectin, fibronectin ED-A, and collagen IValpha1 expression, as well as elevated plasma creatinine levels, were observed after 9 wk. After 2 wk, CTGF mRNA was upregulated threefold in the renal cortex. By 9 wk, CTGF mRNA was also increased in the heart and liver. In contrast, transforming growth factor-beta1 mRNA content was significantly increased only in the kidney by 9 wk. Renal CTGF expression was mainly localized in podocytes and parietal glomerular epithelial cells, and less prominent in mesangial cells. In addition, plasma CTGF levels and urinary CTGF excretion were increased in diabetic mice. Moreover, albuminuria strongly correlated with urinary CTGF excretion (R = 0.83, P < 0.0001). Increased CTGF expression was also demonstrated in type 2 diabetic ob/ob mice, which points to a causal relationship between diabetes and CTGF and thus argues against a role of STZ in this process. The observed relationship of podocyte and urinary CTGF to markers of DN suggests a pathogenic role of CTGF in the development of DN.

Reduction of urinary connective tissue growth factor by Losartan in type 1 patients with diabetic nephropathy

Connective tissue growth factor (CTGF) is an important profibrotic cytokine implicated in development of diabetic glomerulosclerosis. Urinary CTGF is reported to be significantly increased in patients with diabetic nephropathy. The present study aimed to investigate the short- and long term effects of angiotensin II receptor blockade by Losartan on urinary CTGF levels in hypertensive type 1 diabetic patients with diabetic nephropathy. Seventy-one hypertensive type 1 diabetic patients with diabetic nephropathy were included in the study. After a washout period of 4 weeks, the patients received Losartan 50 mg, 100 mg, and 150 mg once daily in treatment periods each lasting 2 months. Thereafter, patients were followed prospectively during treatment with Losartan 100 mg o.d. with a total mean follow-up time of 36 months. At baseline, after 2, 4, and 6 months and then biannually, urinary and plasma CTGF levels [enzyme linked immunosorbent assay (ELISA) fibroGen], albuminuria (Turbidimetry), glomerular filtration rate (GFR) [51-creatinine ethylenediaminetetraacetic acid ((51)Cr-EDTA plasma clearance)] and 24 hours blood pressure (TM2420)) were determined. Baseline levels of urinary and plasma CTGF were 7076 (5708 to 8770) ng/24 hours [geometric mean (95% CI)] and 12.7 (7.3) ng/mL [mean (SD)], respectively. Albuminuria, GFR, and arterial blood pressure at baseline were 1152 (937 to 1416) mg/24 hours, 88 (24) mL/min/1.73 m(2), and 153/80 (17/9) mm Hg, respectively. Losartan significantly reduced urinary CTGF by 21% (9 to 31) (95% CI) initially (P < 0.05 vs. baseline), with no further reduction after increasing dose. The sustained reduction in urinary CTGF was 22% (12 to 32) (P < 0.05 vs. baseline). Rate of decline in GFR during the study was 3.2 (-1.6 to 15.9) mL/min/year [median (range)]. Reduction in urinary CTGF was correlated with a lower rate of decline in GFR (r= 0.23, P= 0.05). Plasma CTGF remained unchanged throughout the study. Our 3-year study demonstrates that Losartan persistently reduces urinary CTGF excretion, which is associated with a slower rate of decline in GFR.