Reduction in connective tissue growth factor by antisense treatment ameliorates renal tubulointerstitial fibrosis

Hideki Yokoi, Masashi Mukoyama, Tetsuya Nagae, Kiyoshi Mori, Takayoshi Suganami, Kazutomo Sawai, Tetsuro Yoshioka, Masao Koshikawa, Takashi Nishida, Masaharu Takigawa, Akira Sugawara, Kazuwa Nakao

Research output: Contribution to journalArticle

207 Citations (Scopus)

Abstract

Connective tissue growth factor (CTGF/CCN2) is one of the candidate factors mediating fibrogenic activity of TGF-β. It was shown previously that the blockade of CTGF by antisense oligonucleotide (ODN) inhibits TGF-β-induced production of fibronectin and type I collagen in cultured renal fibroblasts. The in vivo contribution of CTGF in renal interstitial fibrosis, however, remains to be clarified. With the use of a hydrodynamics-based gene transfer technique, the effects of CTGF antisense ODN are investigated in rat kidneys with unilateral ureteral obstruction (UUO). FITC-labeled ODN injection via the renal vein showed that the ODN was specifically introduced into the interstitium. At day 7 after UUO, the gene expression of CTGF, fibronectin, fibronectin ED-A, and α1(I) collagen in untreated or control ODN-treated obstructed kidneys was prominently upregulated. CTGF antisense ODN treatment, by contrast, markedly attenuated the induction of CTGF, fibronectin, fibronectin ED-A, and α1(I) collagen genes, whereas TGF-β gene upregulation was not affected. The antisense treatment also reduced interstitial deposition of CTGF, fibronectin ED-A, and type I collagen and the interstitial fibrotic areas. The number of myofibroblasts determined by the expression of α-smooth muscle actin was significantly decreased as well. Proliferation of tubular and interstitial cells was not altered with the treatment. These findings indicate that CTGF expression in the interstitium plays a crucial role in the progression of interstitial fibrosis but not in the proliferation of tubular and interstitial cells during UUO. CTGF may become a potential therapeutic target against tubulointerstitial fibrosis.

Original languageEnglish
Pages (from-to)1430-1440
Number of pages11
JournalJournal of the American Society of Nephrology
Volume15
Issue number6
DOIs
Publication statusPublished - Jun 2004

ASJC Scopus subject areas

  • Nephrology

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