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PPAR gamma inhibits growth of rat hepatic stellate cells and TGF beta-induced connective tissue growth factor expression

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Acta Pharmacologica Sinica 2006年第6期27卷 715-723页

作者： Kai SUN Qian WANG~2 Xiao-hui HUANG Department of Hepatobiliary Surgery,the First Affiliated Hospital of Sun Yat-Sen University,Guangzhou 510080,China Department of Hepatobiliary Surgery the First Affiliated Hospital of Sun Yat-Sen University Guangzhou China

Aim:To investigate the effect of peroxisome proliferator-activated receptor gamma(PPARγ)activation on the growth of rat hepatic stellate cells(HSC)and trans-forming growth factor beta(TGF-β)-induced connective tissue growth factor(CTGF)***:After being treated with various amounts of thePPARγ natural ligand 15-deoxy-A 12,14-prostaglandin J2(15-d-PGJ2)or syntheticligand GW7845,the status of HSC proliferation and apoptosis were detected byMTT assay and flow ***,HSC were treated with PPARγ-specific antagonist GW9662 prior to the addition of 15-d-PGJ2or GW7845 andwere subsequently stimulated with TGF-β*** mRNA and protein levels ofCTGF expression were detected by semi-quantitative RT-PCR and Western blot-ting *** changes in the HSC were observed by ***:15-d-PGJ2and GW7845 markedly inhibited HSC prolifera-tion and induced cell apoptosis in a dose-dependent ***,PPARγligands significantly suppressed TGF-β1-induced CTGF expression(at both tran-scriptional and post-transcriptional levels)in HSC,and the inhibitory effect wasdramatically,if not completely,abolished by pretreatment with GW9662,sug-gesting that the inhibition was indeed mediated by PPARγ.Moreover,morpho-logical observation revealed that PPARγ activation caused obvious changes ofHSC from activated to quiescent ***:The PPARγligand hasa potent inhibitory effect on the growth of HSC and TGF-β1-induced CTGFexpression,which makes it a potential antifibrotic candidate for the treatment andprevention of hepatic fibrosis.

关键词： PPAR gamma transforming growth factor beta connective tissue growth factor hepatic stellate cells

Role of connective tissue growth factor in experimental radiation nephropathy in rats

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Chinese Medical Journal 2008年第19期121卷 1925-1931页

作者： LIU Dian-ge WANG Tie-min Department of Nephrology Zhongda Hospital Southeast University School of Medicine Nanjing Jiangsu 210009 China Department of Pediatrics Fourth Clinical Hospital HarbinMedical University Harbin Heilongjiang 150001 China

Background connective tissue growth factor （CTGF） is a potent fibrogenic cytokine which has been associated with progressive glomerulosclerosis and tubulointerstitial fibrosis. We investigated the role of CTGF on the progression of a rat model of radiation nephropathy. Methods The model of radiation nephropathy in rats was established as follows： control group （n=12）, underwent only laparotomy; irradiated group （n=-20）, underwent a laparotomy, then the rats were subjected to a single dose 25 Gy X-ray to the kidneys. The rats were followed up one, three, six and nine months after renal exposure to radiation. Results Renal dysfunction was noted early in irradiated rats. Histological analysis showed focal glomerular sclerotic lesions at an early stage after irradiation. Radiation-induced glomerular and tubulointerstitial injuries were particularly severe the sixth month after irradiation as compared to the control group （P 〈0.01）. By immunohistochemistry, increased expression of CTGF was noted in the irradiated kidneys, which began to increase from the first month after irradiation, and remained significantly higher at the sixth and ninth month after irradiation （P 〈0.01）. Upon Western blot analysis CTGF protein expression showed an increase in the radiation treated kidneys compared with the control rats. The expression of CTGF closely correlated with the progression of radiation nephropathy. The expression of α-smooth muscle actin, vimentin, type Ⅲ collagen and type Ⅳ collagen was also high in the irradiated kidney as compared to control rat kidneys （P 〈0.05）, and was most severe at the sixth and ninth month after irradiation （P 〈0.01）. By double immunostaining, CTGF expressing cells were found to be α-SMA-positive myofibroblasts and vimentin-positive tubular epithelial cells. Glomerular expression of CTGF closely correlated with the glomerular expression of a-SMA （r=0.628, P 〈0.01）, vimentin （r=0.462, P 〈0.05） and accumulation of type IV collagen （r=0.584, P 〈0.01） i

关键词： connective tissue growth factor collagen radiation nephropathy glomerulosclerosis tubulointerstitial fibrosis

Expression of connective tissue growth factor in tumor tissues is an independent predictor of poor prognosis in patients with gastric cancer

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World Journal of Gastroenterology 2008年第13期14卷 2110-2114页

作者： Lu-Ying Liu Yan-Chun Han Shu-Hua Wu Zeng-Hua Lv Department of Pathology Binzhou Medical Collage Binzhou 256603 Shandong Province China Department of Pathology Affiliated Hospital of Binzhou Medical Collage Binzhou 256603 Shandong Province China

AIM: To examine the expression of connective tissue growth factor (CTGF), also known as CCN2, in gastric carcinoma (GC), and the correlation between the expression of CTGF, clinicopathologic features and clinical outcomes of patients with GC. METHODS: One hundred and twenty-two GC patients were included in the present study. All patients were followed up for at least 5 years. Proteins of CTGF were detected using the Powervision two-step immunostaining method. RESULTS: Of the specimens from 122 GC patients analyzed for CTGF expression, 58 (58/122, 47.5%) had a high CTGF expression in cytoplasm of gastric carcinoma cells and 64 (64/122, 52.5%) had a low CTGF expression. Patients with a high CTGF expression showed a higher incidence of lymph node metastasis than those with a low CTGF expression (P = 0.032). Patients with a high CTGF expression had significantly lower 5-year survival rate than those with a low CTGF expression (27.6% vs 46.9%, P = 0.0178), especially those staging Ⅰ+Ⅱ+Ⅲ (35.7% vs 65.2%, P = 0.0027). CONCLUSION: GC patients with an elevated CTGF expression have more lymph node metastases and a shorter survival time. CTGF seems to be an independent prognostic factor for the successful differentiation of high-risk GC patients staging Ⅰ+Ⅱ+Ⅲ. Over-expression of CTGF in human GC cells results in an increased aggressive ability.

关键词： connective tissue growth factor Gastric cancer Prognosis Lymph node metastasis

Molecular evolution of connective tissue growth factor in Cyprinidae (Teleostei:Cypriniformes)

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Progress in Natural Science:Materials International 2008年第2期18卷 155-160页

作者： Xianghui Kong a,b,Xuzhen Wang a,Xiaoni Gan a,Junbing Li a,Shunping He a,a Institute of Hydrobiology,Chinese Academy of Sciences,Wuhan 430072,China b College of Life Science,Henan Normal University,Xinxiang 453007,China Institute of Hydrobiology Chinese Academy of Sciences Wuhan 430072 China College of Life Science Henan Normal University Xinxiang 453007 China

connective tissue growth factor (CTGF) plays an important role in regulation of cell growth,differentiation,apoptosis and individual development in animals. The study of sequences variation and molecular evolution of CTGF gene across various species of the cyprinid could be helpful for understanding of speciation and gene divergence in this kind of fish. In this study,19 novel sequences of CTGF gene were obtained from the representative species of the family Cyprinidae using PCR amplification,cloning and sequencing. Phylogenetic relationships of Cyprinidae were reconstructed by neighbor-joining (NJ),maximum parsimony (MP),maximum likelihood (ML) and Bayesian method. Oryzias latipes from the family Cyprinodontidae was assigned to be the outgroup taxon. Leuciscini and Barbini were clustered into the monophyletic lineages,respectively,with the high nodal supports. The estimation of the ratio of non-synonymous to synonymous substitution (dN/dS) for the various branches indicated that there stood the different evolution rates between the Leuciscini and the Barbini. With the ratio of dN/dS of the Leuciscini being lower than that of the Barbini,species within the Barbini were demonstrated to be subjected to the relatively less selection pressure and under the relaxable evolution background. A 6 bp indel (insertion/deletion) was found at the 50 end of CTGF gene of Cyprinidae,and this 6 bp deletion only appeared in the Leuciscini,which is a typical characteristic of the Leuciscini and provides evidence for the monophylogeny of the Leuciscini. For the amino acid sequences of CTGF protein,the most variations and indels were distributed in the signal region and IGFBP region of this protein,implying that these variations were correlated with the regulation of the CTGF gene expression and protein activity.

关键词： connective tissue growth factor Sequence variation Molecular evolution Cyprinidae

Research progress on the role of connective tissue growth factor in fibrosis of diabetic retinopathy

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International Journal of Ophthalmology(English edition) 2018年第9期11卷 1550-1554页

作者： Teng Ma Li-Jie Dong Xue-Li Du Rui Niu Bo-Jie Hu Tianjin Medical University Eye Hospital Tianjin Medical University Eye InstituteOphthalmology College of Tianjin Medical University

Diabetic retinopathy（DR） is one of the most important types of diabetic microangiopathy, which is a specific change of fundus lesions and is one of the most serious complications of diabetes. When DR develops to proliferative DR, the main factors of decreasing vision, and even blindness, include retinal detachment and vitreous hemorrhage caused by contraction of blood vessels by fiber membrane. Recent studies reported that the formation of fiber vascular membrane is closely related to retinal fibrosis. The connective tissue growth factor（CTGF） is a cytokine that is closely related to DR fibrosis. However, its mechanism is poorly understood. This paper summarizes the recent studies about CTGF on DR fibrosis for a comprehensive understanding of the role and mechanism of CTGF in PDR.

关键词： proliferative diabetic retinopathy fibrosis connective tissue growth factor vascular endothelial growth factor

The Effect of connective tissue growth factor on Human Renal Tubular Epithelial Cell Transdifferentiation

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2004年第4期24卷 350-353页

作者：张春朱忠华邓安国 Department of Nephrology Union Hospital Tongji Medical College Huazhong University of Science and Technology

To investigate the role of connective tissue growth factor (CTGF) in transdifferentiation of human renal tubular epithelial cell (HKC), in vitro cultured HKC cells were divided into 3 groups: negtive control, low dose CTGF-treated group (rh CTGF, 2.5 ng/ml) and high dose CTGF-treated (rhCTGF, 5.0 ng/ml). Then the expression of α-smooth muscle actin (α-SMA) were assessed by indirect immuno-fluorescence, and the percentage of α-SMA positive cells were assessed by flow cytometry. RT-PCR were also performed to examine the mRNA level of α-SMA. Upon the stimulation of different concentrations of rhCTGF, the expression of α-SMA were markedly stronger than that in negative controls. The percentages of α-SMA positive cells were significantly higher in the stimulated groups than that of negative controls (38.9 %, 65.5 % vs 2.4 %, P<0.01) .α-SMA mRNA levels were also up-regulated by the stimulation of rhCTGF (P<0.01). These results suggest that CTGF can promote the transdifferentiation of human renal tubular epithelial cells towards myofibroblast (Myo-F).

关键词： connective tissue growth factor human renal tubular epithelial cell transdifferentiation

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Vascular endothelial growth factor/connective tissue growth factor and proteomic analysis of aqueous humor after intravitreal conbercept for proliferative diabetes retinopathy

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International Journal of Ophthalmology(English edition) 2024年第10期17卷 1816-1827页

作者： Hou-Shuo Li Xiao Lyu Ao Rong Yan-Long Bi Wei Xu Hong-Ping Cui Department of Ophthalmology Tongji HospitalSchool of MedicineTongji UniversityShanghai 200065China Department of Ophthalmology Shanghai East HospitalSchool of MedicineTongji UniversityShanghai 200120China

AIM:To investigate the role of connective tissue growth factor(CTGF)and vascular endothelial growth factor(VEGF)in the protein profile of the aqueous humor in patients with proliferative diabetic retinopathy(PDR)following intravitreal injection of ***:This study included 72 PDR patients and 8 cataract patients as *** patients were divided into 3 groups according to the intervals of 3,5,and 7d between intravitreal conbercept(IVC,0.5 mg/0.05 mL)injection and pars plana vitrectomy(PPV)*** humor samples were collected before and after IVC and PPV for VEGF and CTGF levels detected with enzyme-linked immunosorbent assay(ELISA).The differential proteomics of 10 patients who underwent PPV surgery 5d after IVC and 8 normal controls was studied,Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis were performed on the data,and the protein interaction network of 23 differential proteins was ***:Post-IVC,VEGF levels decreased and CTGF levels increased significantly in aqueous humor,with the CTGF/VEGF ratio rising significantly at all *** chromatography tandem mass spectrometry(LC-MS/MS)identified differentially expressed proteins between preand post-IVC *** and KEGG analyses revealed involvement in immune response,stress response,complement and coagulation cascades,ferroptosis,and PPAR signaling *** analysis highlighted key proteins like APOA1,C3,and transferrin(TF).ELISA assay confirmed the differential expression of proteins such as HBA1,SERPINA1,COL1A1,and ACTB,with significant changes in the IVC ***:The study demonstrates that IVC effectively reduces VEGF levels while increasing CTGF levels,thereby modifying the CTGF/VEGF ratio,and IVC significantly alters the protein profile in the aqueous humor of patients with *** analysis reveals that these changes are associated with critical biological pathways and protein interactions involved in immune respons

关键词： proliferative diabetic retinopathy conbercept vascular endothelial growth factor connective tissue growth factor proteomics

Expression of transcription factors Slug in the lens epithelial cells undergoing epithelial-mesenchymal transition induced by connective tissue growth factor

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International Journal of Ophthalmology(English edition) 2015年第5期8卷 872-876页

作者： Ying-Na Wang Li Qin Jing-Ming Li Li Chen Cheng Pei Medical School of Xi'an Jiaotong University Department of Ophthalmology the First Affiliated HospitalMedical School of Xi'an Jiaotong University

AIMTo investigate the expression of transcription factors Slug in human lens epithelial cells (HLECs) undergoing epithelial-mesenchymal transition (EMT) induced by connective tissue growth factor (CTGF).METHODSHLECs were treated with CTGF of different concentrations (20, 50 and 100 ng/mL) or without CTGF (control) for 24h. The morphological changes of HLECs were analysed by microscopy. The expression and cellular localization of Slug was evaluated by immumo-fluorescence. Expressions of Slug, E-cadherin and alpha smooth muscle actin (α-SMA) were further determined by Western blot *** showed spidle fibrolasts-like characteristics and loosely connected each other after CTGF treatment. The immuno-fluorescence staining indicated that Slug was localized in the nuclei and its expression was induced by CTGF. The relative expressions of Slug protein were 1.64±0.11, 1.96 ±0.03, 3.12 ±0.10, and 4.08±0.14, respectively, in response to control group and treatment with CTGF of 20, 50 and 100 ng/mL (F=443.86, Pfactor Slug may be involved in EMT of HLECs induced by CTGF in vitro.

关键词： transcription factors Slug human lens epithelial cells connective tissue growth factor epithelial-mesenchymal transition alpha smooth muscle actin adhesion molecules E-cadherin

Activation of PPAR-γ Inhibits Differentiation of Rat Osteoblasts by Reducing Expression of connective tissue growth factor

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2014年第5期34卷 652-656页

作者：余维巍夏秦吴艳卜巧云 Department of Geriatrics Tongji HospitalTongji Medical CollegeHuazhong University of Science and Technology

Long-term treatment with an agonist of peroxisome proliferator-activated receptor （PPAR）-γ is associated with bone fractures in the clinical practice. However, the mechanisms underlying the frac- tures are not fully understood. This study was aimed to examine the effect of rosiglitazone （an agonist of PPAR-T） of different doses on the proliferation, differentiation, and transforming growth factor beta 1 （TGF-131）-induced expression of connective tissue growth factor （CTGF） in primary rat osteoblasts in vitro. Osteoblasts were isolated from newly born SD rats and treated with different doses of rosiglita- zone （0-20 gmol/L）. The proliferation and differentiation of osteoblasts were measured by MTT assay and NPP assay, respectively. The expression of CTGF was determined by RT-PCR and Western blotting. The results showed that most isolated osteoblasts displayed strong alkaline phosphatase （ALP） activity and treatment with different doses of rosiglitazone did not affect their proliferation, but significantly in- hibited the differentiation of osteoblasts in a dose-dependent manner. Moreover, treatment with different doses of rosiglitazone significantly reduced the TGF-131-induced CTGF mRNA transcription and protein expression in a dose-dependent manner in rat osteoblasts. It was concluded that the activation of PPAR-y may inhibit the differentiation of osteoblasts by reducing the TGF-131-induced CTGF expres- sion in vitro.

关键词： peroxisome proliferator-activated receptor γ rosiglitazone osteoblasts transforminggrowth factor beta 1 connective tissue growth factor

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