Connective Tissue Growth Factor Expressed in Tubular... : Journal of the American Society of Nephrology (original) (raw)

Pathophysiology of Renal Disease and Progression

Connective Tissue Growth Factor Expressed in Tubular Epithelium Plays a Pivotal Role in Renal Fibrogenesis

Okada, Hirokazu*; Kikuta, Tomohiro*; Kobayashi, Tatsuya*; Inoue, Tsutomu*; Kanno, Yoshihiko*; Takigawa, Masaharu†; Sugaya, Takeshi‡; Kopp, Jeffrey B.§; Suzuki, Hiromichi*

*Department of Nephrology, Saitama Medical College, Saitama; †Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine and Dentistry, Okayama; and ‡Center of Tsukuba Advanced Research Alliance, Institute of Applied Biochemistry, University of Tsukuba, Ibaraki, Japan; and §Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

Address correspondence to: Dr. Hiromichi Suzuki, Department of Nephrology, Saitama Medical College, 38 Morohongo, Moroyama-machi, Irumagun, Saitama 350-0495, Japan. Phone: 81-49-276-1611; Fax: 81-49-295-7338; E-mail address:[email protected]

Accepted September 24, 2004

Received April 30, 2004

Abstract

Connective tissue growth factor (CTGF) is one of the candidate factors that are thought to mediate the downstream profibrotic action of TGF-β. However, its precise role in renal interstitial fibrogenesis has not yet been clarified. It was demonstrated previously that CTGF was expressed in tubular epithelial cells that had been engulfed by interstitial fibrosis in the remnant kidney of the subtotal nephrectomy (SNx) model. In the present study, co-cultures of tubular epithelial cells (mProx24) and tubulointerstitial fibroblasts (TFB) that mimic the subepithelial mesenchyme in the kidney were used to study the profibrotic effects of TGF-β1-induced CTGF. In these co-cultures, TGF-β1 treatment resulted in significantly increased mRNA levels of type I collagen and fibronectin in the TFB. These effects were both direct and indirect, with the latter being mediated by CTGF derived from the co-cultured mProx24. Then TGF-β1 transgenic mice were subtotally nephrectomized and treated with CTGF antisense oligodeoxynucleotide, and their kidneys were analyzed for fibrosis. Intravenous administration of CTGF antisense oligodeoxynucleotide significantly blocked CTGF expression in the proximal tubular epithelial cells in the remnant kidney of these animals despite the sustained level of TGF-β1 mRNA. This reduction in CTGF mRNA level paralleled a reduction in mRNA levels of matrix molecules as well as proteinase inhibitors plasminogen activator inhibitor-1 and tissue inhibitor of metalloproteinase-1, suppressing renal interstitial fibrogenesis. In conclusion, tubular CTGF acts as a downstream mediator of the profibrotic effects of TGF-β1 in the remnant kidney, which is a promising target for antifibrotic drugs designed to treat TGF-β1-dependent interstitial fibrosis.