Fibroblast expression of an IκB dominant-negative transgene attenuates renal fibrosis.
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 ((p)p65) 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;IκBdN 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.
Inoue
Tsutomu
T
Department of Nephrology, Faculty of Medicine, Saitama Medical University, Saitama, Japan.
Takenaka
Tsuneo
T
Hayashi
Matsuhiko
M
Monkawa
Toshiaki
T
Yoshino
Jun
J
Shimoda
Kouji
K
Neilson
Eric G
EG
Suzuki
Hiromichi
H
Okada
Hirokazu
H
D000818:Animals; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation; D020672:I-kappa B Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D007150:Immunohistochemistry; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity; D019076:Transgenes
D020672:I-kappa B Proteins; C000606205:Nfkbia protein, mouse; D012333:RNA, Messenger; D000072000:NF-KappaB Inhibitor alpha