Aldosterone/Mineralocorticoid receptor stimulation induces cellular senescence in the kidney.

Abstract

Recent studies demonstrated a possible role of aldosterone in mediating cell senescence. Thus, the aim of this study was to investigate whether aldosterone induces cell senescence in the kidney and whether aldosterone-induced renal senescence affects the development of renal injury. Aldosterone infusion (0.75 μg/h) into rats for 5 weeks caused hypertension and increased urinary excretion rates of proteins and N-acetyl-β-D-glucosaminidase. Aldosterone induced senescence-like changes in the kidney, exhibited by increased expression of the senescence-associated β-galactosidase, overexpression of p53 and cyclin-dependent kinase inhibitor (p21), and decreased expression of SIRT1. These changes were abolished by eplerenone (100 mg/kg/d), a mineralocorticoid receptor (MR) antagonist, but unaffected by hydralazine (80 mg/liter in drinking water). Furthermore, aldosterone induced similar changes in senescence-associated β-galactosidase, p21, and SIRT1 expression in cultured human proximal tubular cells, which were normalized by an antioxidant, N-acetyl L-cysteine, or gene silencing of MR. Aldosterone significantly delayed wound healing and reduced the number of proliferating human proximal tubular cells, while gene silencing of p21 diminished the effects, suggesting impaired recovery from tubular damage. These findings indicate that aldosterone induces renal senescence in proximal tubular cells via the MR and p21-dependent pathway, which may be involved in aldosterone-induced renal injury.

• Authors: Yu-Yan Fan, Masakazu Kohno, Hirofumi Hitomi, Kento Kitada, Yoshihide Fujisawa, Junichi Yatabe, Midori Yatabe, Robin A Felder, Hiroyuki Ohsaki, Kazi Rafiq, Shamshad J Sherajee, Takahisa Noma, Akira Nishiyama, Daisuke Nakano
• Journal: Endocrinology (Endocrinology) Vol. 152 Issue 2 Pg. 680-8 (Feb 2011) ISSN: 1945-7170 [Electronic] United States
• PMID: 21190955 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclin-Dependent Kinase Inhibitor p21
• Mineralocorticoid Receptor Antagonists
• Receptors, Mineralocorticoid
• Tumor Suppressor Protein p53
• Hydralazine
• Spironolactone
• Aldosterone
• Eplerenone
• Acetylglucosaminidase
• Sirtuin 1

Topics

• Acetylglucosaminidase (urine)
• Aldosterone (administration & dosage, pharmacology)
• Animals
• Blood Pressure (drug effects)
• Blotting, Western
• Cells, Cultured
• Cellular Senescence (drug effects, genetics)
• Cyclin-Dependent Kinase Inhibitor p21 (genetics)
• Eplerenone
• Humans
• Hydralazine (pharmacology)
• Hypertension (chemically induced)
• Kidney (cytology, drug effects, metabolism)
• Male
• Mineralocorticoid Receptor Antagonists
• RNA Interference
• Rats
• Rats, Sprague-Dawley
• Receptors, Mineralocorticoid (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Sirtuin 1 (genetics)
• Spironolactone (analogs & derivatives, pharmacology)
• Tumor Suppressor Protein p53 (genetics)