ACE-Dependent and chymase-dependent angiotensin II generation in normal and glucose-stimulated human mesangial cells

ACE-Dependent and chymase-dependent angiotensin II generation in normal and glucose-stimulated human mesangial cells

Author Cristovam, Priscila C. Autor UNIFESP Google Scholar
Arnoni, Carine P. Autor UNIFESP Google Scholar
De Andrade, Maria Claudina C. Autor UNIFESP Google Scholar
Casarini, Dulce E. Autor UNIFESP Google Scholar
Pereira, Luciana G. Autor UNIFESP Google Scholar
Schor, Nestor Autor UNIFESP Google Scholar
Boim, Mirian A. Autor UNIFESP Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
Abstract High glucose (HG) increases angiotensin II (AngII) generation in mesangial cells (MC). Chymase, an alternative AngII-generating enzyme, is upregulated in the glomeruli of diabetic kidneys. in this study, we examined AngII synthesis by human MC via anglotensin-converting enzyme (ACE)-dependent and chymase-dependent pathways under normal glucose (NG, 5 mM) and HG (30 mM) conditions. NG cells expressed ACE and chymase mRNA. Under NG conditions the chymase inhibitor chymostatin reduced AngII levels in cell lysates and in the culture medium, and the ACE inhibitor captopril had no effect. HG induced a 3-fold increase in chymase mRNA and protein but not in ACE mRNA; however, HG induced a 10-fold increase in intracellular ACE activity. the increase in AngII generation induced by HG was found in the cell lysate but not in the culture medium. the rise in intracellular AngII was not prevented by captopril or by chymostatin. Moreover, captopril inhibited extracellular ACE activity but failed to block intracellular ACE activity; these results suggested that captopril was unable to reach intracellular ACE. Losartan did not change the intracellular AngII content in either NG or HG conditions, and this lack of change suggested that the increase in AngII was due to intracellular generation. Together these results suggest that chymase may be active in human MC and that both ACE and chymase are involved in increased AngII generation during the HG stimulus by different mechanisms, including an upregulation of chymase mRNA and a rise in intracellular ACE activity, favoring the generation and accumulation of intracellular AngII.
Keywords captopril
diabetic nephropathy
Language English
Date 2008-08-01
Published in Experimental Biology and Medicine. Maywood: Soc Experimental Biology Medicine, v. 233, n. 8, p. 1035-1043, 2008.
ISSN 1535-3702 (Sherpa/Romeo, impact factor)
Publisher Soc Experimental Biology Medicine
Extent 1035-1043
Access rights Closed access
Type Article
Web of Science ID WOS:000257979400014

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