Spironolactone increases integrin beta3 gene expression in kidney and heart muscle cells.
In clinical trials of heart failure, spironolactone, an antagonist of the mineralocorticoid receptor (MR), reduced mortality rates by unknown mechanisms. We hypothesized that spironolactone functions by upregulating expression of certain cardiovascular genes. An RNA differential display technique was used to identify genes whose expression was increased by spironolactone in an Xenopus kidney epithelial cell line (A6), a known target of aldosterone. We found that integrin beta3 gene expression was increased by spironolactone, and reversed by aldosterone or dexamethasone in a dose dependent manner. Competition binding studies and RT-PCR indicate the presence of MR in A6 cells, suggesting that regulation of expression occurred primarily through MR. Spironolactone also increased integrin beta3 expression in rat neonatal cardiomyocytes. In summary, spironolactone increases integrin beta3 gene expression in kidney epithelial cells and cardiomyocytes. The findings suggest new mechanisms for spironolactone actions with possible relevance to treatment of heart disease.
Chun
Tae-Yon
TY
Department of Medicine, Indiana University School of Medicine and the VA Medical Center, 541 Clinical Drive, Indianapolis, IN 46202, USA.
Bloem
Laura
L
Pratt
J Howard
JH
D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001667:Binding, Competitive; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D039661:Integrin beta3 / Q000096:biosynthesis* / Q000187:drug effects; D007668:Kidney / Q000166:cytology / Q000378:metabolism*; D000451:Mineralocorticoid Receptor Antagonists; D032383:Myocytes, Cardiac / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000502:physiology*; D013148:Spironolactone / Q000494:pharmacology*; D014981:Xenopus
D039661:Integrin beta3; D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000450:Aldosterone; D003907:Dexamethasone