Connective Tissue Growth Factor is a Biomarker and Mediator of Kidney Allograft Fibrosis

• Published in: American journal of transplantation Vol. 6; no. 10; pp. 2292 - 2306
• Main Authors: Cheng, O., Thuillier, R., Sampson, E., Schultz, G., Ruiz, P., Zhang, X., Yuen, P.S.T., Mannon, R.B.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-10-2006; Blackwell
• Subjects: Animals; Biological and medical sciences; Biomarkers - metabolism; Biopsy; Blotting, Western; Cells, Cultured; Chronic allograft nephropathy; Connective Tissue Growth Factor; CTGF; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; fibrosis; Fibrosis - complications; Fibrosis - metabolism; Fibrosis - pathology; Gene Expression; Graft Rejection - complications; Graft Rejection - metabolism; Graft Rejection - pathology; Humans; Immediate-Early Proteins - genetics; Immediate-Early Proteins - immunology; Immediate-Early Proteins - metabolism; Insulin-Like Growth Factor Binding Proteins - metabolism; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - immunology; Intercellular Signaling Peptides and Proteins - metabolism; kidney; Kidney Failure, Chronic - etiology; Kidney Failure, Chronic - metabolism; Kidney Failure, Chronic - pathology; Kidney Transplantation - pathology; Kidney Tubules - pathology; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; mouse; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Polymerase Chain Reaction; Renal failure; RNA, Messenger - genetics; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; TGF‐β; transplantation; Transplantation, Homologous; Transforming growth factor β; Homograft; Biological marker; Transplantation; Homotransplantation; CTGF; kidney; Surgery; Graft; TGF-β; Kidney disease; Chronic allograft nephropathy; Urinary system disease; Rodentia; Connective tissue growth factor; Rejection; Vertebrata; Chronic; Mammalia; Nephropathy; Treatment; Mouse; Animal; Fibrosis; Renal failure; Mediator
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2006.01493.x

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 α‐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‐β. 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.
Connective tissue growth factor is demonstrable systemically and locally in mouse kidney allografts undergoing progressive inflammation and fibrosis, and is elevated in serum and urine of human transplant recipients, suggesting that it is compatible with it having a critical role in graft fibrogenesis.