Premium
Effects of AT 1 Receptor‐Mediated Endocytosis of Extracellular Ang II on Activation of Nuclear Factor‐κB in Proximal Tubule Cells
Author(s) -
ZHUO JIA L.,
CARRETERO OSCAR A.,
LI XIAO C.
Publication year - 2006
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1378.078
Subject(s) - angiotensin ii , losartan , receptor , endocytosis , proinflammatory cytokine , chemistry , endocrinology , medicine , microbiology and biotechnology , biology , biochemistry , inflammation
Angiotensin II (Ang II) exerts powerful proinflammatory and growth effects on the development of Ang II‐induced hypertensive glomerulosclerosis and tubulo‐interstitial fibrosis. The proinflammatory and growth actions of Ang II are primarily mediated by activation of cell surface type 1 receptors (AT 1 ) and the transcription factor nuclear factor‐κB (NF‐κB). However, binding of cell surface receptors by extracellular Ang II also induces receptor‐mediated endocytosis of the agonist‐receptor complex in renal cells. The purpose of the present study was to determine whether AT 1 receptor‐mediated endocytosis of extracellular Ang II is required for Ang II‐induced NF‐κB activation and subsequent proliferation of rabbit renal proximal tubule cells. Expression of AT 1 (primarily AT 1a or human AT 1 ) receptors in these cells was confirmed by Western blot, showing that transfection of a human AT 1 receptor‐specific 20‐25 nucleotide siRNA knocked down more than 70% of AT 1 receptor protein ( P < 0.01). Stimulation of proximal tubule cells by Ang II (1 nM) induced fourfold increases in NF‐κB activity ( P < 0.01). The Ang II‐increased NF‐κB activity was significantly attenuated by coadministration of losartan (10 μM), an AT 1 receptor‐selective blocker, or colchicine (1 μM), a selective cytoskeleton microtubule inhibitor known to block receptor‐mediated endocytosis ( P < 0.01). Furthermore, Ang II significantly increased 3 H‐thymidine incorporation (>55%, P < 0.01), an index of cell proliferation and DNA synthesis, and the effect was also attenuated by coadministration of losartan and colchicine ( P < 0.01). Our results therefore suggest that AT 1 receptor‐mediated endocytosis of extracellular Ang II may be required for Ang II‐induced NF‐κB activation and subsequent cell proliferation in renal proximal tubule cells.