Aldosterone induces p21-regulated apoptosis via increased synthesis and secretion of tumour necrosis factor-α in human proximal tubular cells.

Abstract

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
• Journal: Clinical and experimental pharmacology & physiology (Clin Exp Pharmacol Physiol) Vol. 39 Issue 10 Pg. 858-63 (Oct 2012) ISSN: 1440-1681 [Electronic] Australia
• PMID: 23013131 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 The Authors Clinical and Experimental Pharmacology and Physiology © 2012 Wiley Publishing Asia Pty Ltd.

Chemical References

• Apoptosis Regulatory Proteins
• Cyclin-Dependent Kinase Inhibitor p21
• Tumor Necrosis Factor-alpha
• Aldosterone
• beta-Galactosidase

Topics

• Aldosterone (metabolism, pharmacology)
• Apoptosis (drug effects, physiology)
• Apoptosis Regulatory Proteins (metabolism)
• Cells, Cultured
• Cellular Senescence (drug effects, physiology)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Humans
• Kidney (cytology)
• Kidney Tubules, Proximal (cytology, drug effects, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• beta-Galactosidase (metabolism)