Activation of NF-κB in Tubular Epithelial Cells of Rats With Intense Proteinuria
Hypertension(2001)
Abstract
Abstract —The mechanisms by which persistent proteinuria induces interstitial inflammation and fibrosis are not well known, although nuclear factor-κB (NF-κB), which regulates the transcription of many genes involved in renal injury, could be implicated. In rats with intense proteinuria, we studied the renal activation of NF-κB as well as the potential involvement of the vasoactive hormones angiotensin II (Ang II) and endothelin-1 (ET-1). Uninephrectomized Wistar-Kyoto rats receiving 1 g/d of BSA had proteinuria but no renal morphological lesions at day 1. By contrast, tubular atrophy and/or dilation and mononuclear cell infiltration were observed after 8 or 28 days of BSA administration, coinciding with maximal proteinuria. In relation to control uninephrectomized rats, the renal cortex of nephritic rats showed an increment in the activation of NF-κB at all time periods studied. By in situ Southwestern histochemistry, NF-κB activity was mainly localized in proximal tubules, interstitial mononuclear cells, and, to a lesser extent, the glomeruli. The administration of the ACE inhibitor quinapril plus the ET A /ET B receptor antagonist bosentan during 28 days to BSA-overloaded animals diminished proteinuria, renal lesions, and NF-κB activity more markedly than single drugs. Cultured tubular epithelial cells exposed to BSA revealed an intense NF-κB activation in a time- and dose-dependent manner. Incubation of cells with receptor antagonists of Ang II (AT 1 : losartan and AT 2 : PD-123,319) or ET-1 (ET A : BQ123 and ET B : IRL1038) inhibited significantly the BSA-induced NF-κB activity (90%, 75%, 90%, and 60% of inhibition versus basal, respectively). Our results show that overload proteinuria causes NF-κB activation in tubular epithelial cells both in vivo and in vitro. The vasoactive peptides Ang II and ET-1 appear to be implicated in this effect. The results reveal a novel mechanism of perpetuation of renal damage induced by persistent proteinuria.
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