Abstract
ANG II has been shown to modulate kidney cell growth and contribute to the pathobiology of glomerulosclerosis. Glomerular visceral epithelial cell (GEC) injury or loss is considered to play a pivotal role in the initiation and progression of glomerulosclerosis. In the present study, we investigated the effect of ANG II on GEC apoptosis. Rat GECs were incubated with increasing doses of ANG II for variable time periods. Apoptosis was evaluated by cell nucleus staining and DNA fragmentation assay. ANG II induced GEC apoptosis in a dose- and time-dependent manner. The proapoptotic effect was attenuated by the ANG II receptor type 1 antagonist losartan or the ANG II receptor type 2 antagonist PD-123319 and was completely blocked by incubation with the combined antagonists. Moreover, ANG II stimulated transforming growth factor (TGF)-beta1 production as measured by ELISA. GECs exposed to TGF-beta1 demonstrated a dose- and time-dependent increase in apoptosis. ANG II-induced apoptosis was significantly inhibited by addition of anti-TGF-beta1 antibody. ANG II also upregulated the expression of Fas, FasL, and Bax and downregulated the expression of Bcl-2 in GECs. These studies suggest that ANG II induces GEC apoptosis by a mechanism involving TGF-beta1 expression that may, importantly, contribute to the pathogenesis of glomerulosclerosis.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Angiotensin II / pharmacology*
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Angiotensin Receptor Antagonists
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Animals
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Antibodies / pharmacology
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Antihypertensive Agents / pharmacology
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Cells, Cultured
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DNA Fragmentation / drug effects*
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Epithelial Cells / cytology
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Epithelial Cells / drug effects*
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Epithelial Cells / metabolism
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Fas Ligand Protein
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Imidazoles / pharmacology
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Kidney Glomerulus / cytology*
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Kidney Glomerulus / metabolism
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Losartan / pharmacology
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Membrane Glycoproteins / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Pyridines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptor, Angiotensin, Type 1
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Receptor, Angiotensin, Type 2
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Receptors, Angiotensin / metabolism
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Transforming Growth Factor beta / biosynthesis
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Transforming Growth Factor beta / immunology
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Transforming Growth Factor beta1
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Vasoconstrictor Agents / pharmacology*
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bcl-2-Associated X Protein
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fas Receptor / metabolism
Substances
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Angiotensin Receptor Antagonists
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Antibodies
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Antihypertensive Agents
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Bax protein, rat
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Fas Ligand Protein
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Faslg protein, rat
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Imidazoles
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Membrane Glycoproteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Pyridines
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Receptor, Angiotensin, Type 1
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Receptor, Angiotensin, Type 2
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Receptors, Angiotensin
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Tgfb1 protein, rat
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Vasoconstrictor Agents
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bcl-2-Associated X Protein
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fas Receptor
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Angiotensin II
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PD 123319
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Losartan