Document Detail


Aldosterone induces p21-regulated apoptosis via increased synthesis and secretion of tumour necrosis factor-α in human proximal tubular cells.
MedLine Citation:
PMID:  23013131     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
1. Aldosterone has been shown to mediate p21-dependent cellular senescence in rat kidney proximal tubules in vivo and in cultured human proximal tubular cells. The p21-induced senescent cells express higher levels of apoptotic cytokines, such as tumour necrosis factor (TNF)-α compared with non-senescent cells. The aim of the present study was to investigate the hypothesis that aldosterone increases proximal tubular apoptosis by increasing the secretion of apoptosis-inducing factors through a p21-dependent mechanism. 2. Human proximal tubular cells were incubated with aldosterone (10 nmol/L) and cell senescence was detected by senescence-associated β-galactosidase staining and expression of p21. Apoptosis was analysed by terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling and annexin/propidium iodide staining, whereas p21 localization was determined by immunofluorescence. 3. Exposure of cells to aldosterone for 3 or 5 days increased senescence-associated β-galactosidase staining, p21 and TNF-α mRNA expression and secretion of TNF-α into the culture medium. These changes were abolished by gene silencing of p21. Aldosterone failed to increase the number of apoptotic cells on day 3, but did increase them on day 5. A neutralizing antibody against TNF-α prevented the aldosterone-induced apoptotic changes. Aldosterone did not affect localization of p21. 4. These findings indicate that aldosterone increases TNF-α synthesis and secretion in proximal tubular cells via p21/senescence-dependent cell phenotypic changes and that the TNF-α secreted plays an important role as a paracrine factor in mediating cell apoptosis, indicating a possible involvement in aldosterone-induced renal damage.
Authors:
Kento Kitada; Daisuke Nakano; Hirofumi Hitomi; Hiroyuki Kobori; Kazushi Deguchi; Hirohito Mori; Tsutomu Masaki; Akira Nishiyama
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Clinical and experimental pharmacology & physiology     Volume:  39     ISSN:  1440-1681     ISO Abbreviation:  Clin. Exp. Pharmacol. Physiol.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-09-27     Completed Date:  2013-05-15     Revised Date:  2013-10-09    
Medline Journal Info:
Nlm Unique ID:  0425076     Medline TA:  Clin Exp Pharmacol Physiol     Country:  Australia    
Other Details:
Languages:  eng     Pagination:  858-63     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors Clinical and Experimental Pharmacology and Physiology © 2012 Wiley Publishing Asia Pty Ltd.
Affiliation:
Department of Pharmacology, Kagawa University, Kagawa, Japan.
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MeSH Terms
Descriptor/Qualifier:
Aldosterone / metabolism,  pharmacology*
Apoptosis / drug effects*,  physiology
Apoptosis Regulatory Proteins / metabolism*
Cell Aging / drug effects,  physiology
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
Humans
Kidney / cytology
Kidney Tubules, Proximal / cytology,  drug effects*,  metabolism*
Tumor Necrosis Factor-alpha / metabolism*
beta-Galactosidase / metabolism
Grant Support
ID/Acronym/Agency:
R01 DK072408/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Tumor Necrosis Factor-alpha; 52-39-1/Aldosterone; EC 3.2.1.23/beta-Galactosidase
Comments/Corrections

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