(Hypertension. 2001;37:1171.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Activation of NF-
B in Tubular Epithelial Cells of Rats With Intense Proteinuria
Role of Angiotensin II and Endothelin-1
From the Renal and Vascular Research Laboratory (D.G.-G., R.L., N.T., J.E.), Department of Pathology (J.F., F.M.), Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.
Correspondence to Jesús Egido, MD, Renal and Vascular Laboratory, Fundación Jiménez Díaz, Avda Reyes Católicos 2, 28040-Madrid, Spain. E-mail ehiper{at}fjd.es
Abstract—The
mechanisms by which persistent proteinuria induces
interstitial inflammation and fibrosis are not well known,
although nuclear factor-
B (NF-B), 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-B 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-B at all time periods studied. By
in situ Southwestern histochemistry, NF-B 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
ETA/ETB receptor
antagonist bosentan during 28 days to BSA-overloaded
animals diminished proteinuria, renal lesions, and NF-B activity
more markedly than single drugs. Cultured tubular epithelial cells
exposed to BSA revealed an intense NF-B activation in a time- and
dose-dependent manner. Incubation of cells with receptor
antagonists of Ang II (AT1:
losartan and AT2: PD-123,319) or ET-1
(ETA: BQ123 and ETB:
IRL1038) inhibited significantly the BSA-induced NF-B activity
(90%, 75%, 90%, and 60% of inhibition versus basal, respectively).
Our results show that overload proteinuria causes NF-B 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.
Key Words: proteinuria • epithelium • renal disease • angiotensin II • endothelin
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