Gene transfer of truncated IkappaBalpha prevents tubulointerstitial injury.
BACKGROUND
Severe proteinuria not only indicates the presence of progressive glomerular disease, but also causes tubular epithelial cells to produce inflammatory mediators leading to tubulointerstitial (TI) injury. We investigated the role of nuclear factor-kappaB (NF-kappaB) in tubular epithelial cells in the development of proteinuria-induced TI injury.


METHODS
To specifically inhibit NF-kappaB activation, a recombinant adenovirus vector expressing a truncated form of IkappaBalpha (AdexIkappaBDeltaN) was injected into renal arteries of protein-overloaded rats, a model of TI injury characterized by infiltration of mononuclear cells and fibrosis.


RESULTS
Activation of NF-kappaB in the renal cortex, observed in protein-overloaded rats treated with a control vector, recombinant lacZ adenovirus, was prevented in AdexIkappaBDeltaN-injected rats. Microscopic examination revealed AdexIkappaBDeltaN treatment to markedly attenuate proteinuria-induced TI injury. Increased immunostaining of vascular cell adhesion molecule-1, transforming growth factor-beta, and fibronectin in TI lesions also was suppressed by AdexIkappaBDeltaN injection.


CONCLUSIONS
These findings provide evidence of the critical role of NF-kappaB activation in TI injury and suggest the therapeutic potential of adenovirus-mediated IkappaBDeltaN gene transfer into the kidney as a means of interrupting the process of TI damage.
Takase
Osamu
O
Department of Internal Medicine, Keio University Medical School, Tokyo, Japan.
Hirahashi
Junichi
J
Takayanagi
Atsushi
A
Chikaraishi
Akihiro
A
Marumo
Takeshi
T
Ozawa
Yuri
Y
Hayashi
Matsuhiko
M
Shimizu
Nobuyoshi
N
Saruta
Takao
T
D000818:Animals; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D020672:I-kappa B Proteins / Q000235:genetics* / Q000494:pharmacology*; D007672:Kidney Cortex / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology; D011507:Proteinuria / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics
D005353:Fibronectins; D020672:I-kappa B Proteins; D016328:NF-kappa B; D010446:Peptide Fragments; D016212:Transforming Growth Factor beta; D019010:Vascular Cell Adhesion Molecule-1; D001616:beta-Galactosidase