Connective tissue growth factor expressed in tubular epithelium plays a pivotal role in renal fibrogenesis.
Connective tissue growth factor (CTGF) is one of the candidate factors that are thought to mediate the downstream profibrotic action of TGF-beta. 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-beta1-induced CTGF. In these co-cultures, TGF-beta1 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-beta1 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-beta1 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-beta1 in the remnant kidney, which is a promising target for antifibrotic drugs designed to treat TGF-beta1-dependent interstitial fibrosis.
Okada
Hirokazu
H
Department of Nephrology, Saitama Medical College, 38 Morohongo, Moroyama-machi, Irumagun, Saitama 350-0495, Japan.
Kikuta
Tomohiro
T
Kobayashi
Tatsuya
T
Inoue
Tsutomu
T
Kanno
Yoshihiko
Y
Takigawa
Masaharu
M
Sugaya
Takeshi
T
Kopp
Jeffrey B
JB
Suzuki
Hiromichi
H
D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D055513:Connective Tissue Growth Factor; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000473:pathology* / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009395:Nephritis, Interstitial / Q000473:pathology / Q000503:physiopathology*; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
C526318:CCN2 protein, mouse; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D016326:Extracellular Matrix Proteins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D011994:Recombinant Proteins; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor