Fibroblast expression of an IκB dominant-negative transgene attenuates renal fibrosis

Tsutomu Inoue, Tsuneo Takenaka, Matsuhiko Hayashi, Toshiaki Monkawa, Jun Yoshino, Kouji Shimoda, Eric G. Neilson, Hiromichi Suzuki, Hirokazu Okada

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Abstract

It is not clear whether interstitial fibroblasts or tubular epithelial cells are primarily responsible for the profibrotic effects of NF-κB activation during renal fibrogenesis. Here, we crossed mice carrying a conditional IκB dominant-negative transgene (IκBdN) with mice transgenic for cell-specific FSP1.Cre (FSP1+ fibroblasts) or γGT.Cre (proximal tubular epithelia) and challenged all progeny with unilateral ureteral obstruction. We determined NF-κB activation by nuclear localization of phosphorylated p65 (pp65) in renal tissues after 7 days. We observed inhibition of NF-κB activation in interstitial cells and tubular epithelia in obstructed kidneys of FSP1.Cre;IκBdN and γGT.Cre;IκBdN mice, respectively, compared with IκBdN controls (P<0.05). Deposition of extracellular matrix, however, was significantly lower in the obstructed kidneys of FSP1.Cre;IκBdN mice but not in γGT.Cre;IκBdN mice (P < 0.05). In addition, levels of mRNA encoding the profibrotic PAI-1, fibronectin-EIIIA, and type I (α1) procollagen were significantly lower in obstructed kidneys of FSP1.Cre;I κBdN mice compared with γGT.Cre;IκBdN mice (P < 0.05). Taken together, these data support a profibrotic role for fibroblasts, but not proximal tubular epithelial cells, in modulating NF-κB activation during renal fibrogenesis.

Original languageEnglish
Pages (from-to)2047-2052
Number of pages6
JournalJournal of the American Society of Nephrology
Volume21
Issue number12
DOIs
Publication statusPublished - 2010 Dec

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Transgenes
Fibrosis
Fibroblasts
Kidney
Epithelium
Epithelial Cells
Ureteral Obstruction
Plasminogen Activator Inhibitor 1
Collagen Type I
Fibronectins
Transgenic Mice
Extracellular Matrix
Messenger RNA

ASJC Scopus subject areas

  • Nephrology

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Fibroblast expression of an IκB dominant-negative transgene attenuates renal fibrosis. / Inoue, Tsutomu; Takenaka, Tsuneo; Hayashi, Matsuhiko; Monkawa, Toshiaki; Yoshino, Jun; Shimoda, Kouji; Neilson, Eric G.; Suzuki, Hiromichi; Okada, Hirokazu.

In: Journal of the American Society of Nephrology, Vol. 21, No. 12, 12.2010, p. 2047-2052.

Research output: Contribution to journalArticle

Inoue, Tsutomu ; Takenaka, Tsuneo ; Hayashi, Matsuhiko ; Monkawa, Toshiaki ; Yoshino, Jun ; Shimoda, Kouji ; Neilson, Eric G. ; Suzuki, Hiromichi ; Okada, Hirokazu. / Fibroblast expression of an IκB dominant-negative transgene attenuates renal fibrosis. In: Journal of the American Society of Nephrology. 2010 ; Vol. 21, No. 12. pp. 2047-2052.
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