Abstract |
Connective tissue growth factor (CTGF/CCN2) is one of the candidate factors mediating fibrogenic activity of TGF-beta. It was shown previously that the blockade of CTGF by antisense oligonucleotide (ODN) inhibits TGF-beta-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 alpha1(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 alpha1(I) collagen genes, whereas TGF-beta 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 alpha-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.
|
Authors | Hideki Yokoi, Masashi Mukoyama, Tetsuya Nagae, Kiyoshi Mori, Takayoshi Suganami, Kazutomo Sawai, Tetsuro Yoshioka, Masao Koshikawa, Takashi Nishida, Masaharu Takigawa, Akira Sugawara, Kazuwa Nakao |
Journal | Journal of the American Society of Nephrology : JASN
(J Am Soc Nephrol)
Vol. 15
Issue 6
Pg. 1430-40
(Jun 2004)
ISSN: 1046-6673 [Print] United States |
PMID | 15153554
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Actins
- CCN2 protein, rat
- Fibronectins
- Immediate-Early Proteins
- Intercellular Signaling Peptides and Proteins
- Oligonucleotides
- Oligonucleotides, Antisense
- Connective Tissue Growth Factor
|
Topics |
- Actins
(biosynthesis)
- Animals
- Blotting, Northern
- Blotting, Western
- Cell Division
- Connective Tissue Growth Factor
- Fibronectins
(biosynthesis)
- Fibrosis
(metabolism)
- Gene Transfer Techniques
- Immediate-Early Proteins
(biosynthesis)
- Immunohistochemistry
- Intercellular Signaling Peptides and Proteins
(biosynthesis)
- Kidney
(metabolism)
- Kidney Diseases
(metabolism)
- Male
- Microscopy, Fluorescence
- Muscle, Smooth
(metabolism)
- Oligonucleotides
(chemistry)
- Oligonucleotides, Antisense
(chemistry, pharmacology)
- Plasmids
(metabolism)
- Rats
- Rats, Wistar
- Signal Transduction
- Transfection
- Up-Regulation
- Ureteral Obstruction
|