title: Connective tissue growth factor is a biomarker and mediator of kidney allograft fibrosis.
abstract: Chronic allograft nephropathy (CAN) is a leading cause of kidney graft failure following transplantation. Its causes are complex and include both immunological and nonimmunological factors. Here we have studied the development of CAN in a mouse model of kidney transplantation comparing isografts and allografts. Unlike the normal histology and normal serum creatinine of the uninephrectomized, nonrejecting isografted mice (0.219 +/- 0.024 mg/dL), allografted mice demonstrated severe renal dysfunction (mean serum creatinine 0.519 +/- 0.061 mg/dL; p < 0.005) with progressive inflammation and fibrosis of the kidney. These animals also showed an increased expression of connective tissue growth factor (CTGF), both systemically and within the graft. CTGF was highly expressed in tubuloepithelial cells of allografts, along with alpha-smooth muscle actin, a marker of myofibroblasts, and transcriptionally associated with other markers of fibrosis. In vitro studies of tubular epithelium indicate that CTGF is capable of inducing EMT, independent of TGF-beta. Finally, in human transplant recipients, serum and urine CTGF levels are significantly elevated compared to naïve individuals. Urinary levels correlated with the histological presence of CAN. These studies suggest a critical role of CTGF in graft fibrogenesis, for both mouse and man. Thus, CTGF has potential as a biomarker of CAN, and also a therapeutic target in managing graft fibrosis.
authors.affiliation: Transplantation Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: O
authors.initials: O
authors.lastname: Cheng
authors.forename: R
authors.initials: R
authors.lastname: Thuillier
authors.forename: E
authors.initials: E
authors.lastname: Sampson
authors.forename: G
authors.initials: G
authors.lastname: Schultz
authors.forename: P
authors.initials: P
authors.lastname: Ruiz
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: P S T
authors.initials: PS
authors.lastname: Yuen
authors.forename: R B
authors.initials: RB
authors.lastname: Mannon
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D015153:Blotting, Western; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005355:Fibrosis / Q000150:complications / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006084:Graft Rejection / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation / Q000473:pathology*; D007684:Kidney Tubules / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D014184:Transplantation, Homologous
chemical_list: D015415:Biomarkers; C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; D017874:Immediate-Early Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D055513:Connective Tissue Growth Factor