Activation of NF-kappaB in tubular epithelial cells of rats with intense proteinuria: role of angiotensin II and endothelin-1.
The mechanisms by which persistent proteinuria induces interstitial inflammation and fibrosis are not well known, although nuclear factor-kappaB (NF-kappaB), 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-kappaB 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-kappaB at all time periods studied. By in situ Southwestern histochemistry, NF-kappaB 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-kappaB activity more markedly than single drugs. Cultured tubular epithelial cells exposed to BSA revealed an intense NF-kappaB 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-kappaB activity (90%, 75%, 90%, and 60% of inhibition versus basal, respectively). Our results show that overload proteinuria causes NF-kappaB 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.
Gómez-Garre
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D
Renal and Vascular Research Laboratory, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.
Largo
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Tejera
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Fortes
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Manzarbeitia
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Egido
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D000704:Analysis of Variance; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001284:Atrophy; D002460:Cell Line; D019332:Endothelin-1 / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D007672:Kidney Cortex / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D009392:Nephrectomy; D009393:Nephritis / Q000473:pathology* / Q000652:urine*; D011507:Proteinuria / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY
D019332:Endothelin-1; D016328:NF-kappa B; D000804:Angiotensin II