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.
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