title: 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.affiliation: Department of Cardiorenal and Cerebrovascular Medicine, Life Sciences Research Center, Kagawa University, Kagawa 761-0793, Japan.
authors.forename: Yu-Yan
authors.initials: YY
authors.lastname: Fan
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohno
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hitomi
authors.forename: Kento
authors.initials: K
authors.lastname: Kitada
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Fujisawa
authors.forename: Junichi
authors.initials: J
authors.lastname: Yatabe
authors.forename: Midori
authors.initials: M
authors.lastname: Yatabe
authors.forename: Robin A
authors.initials: RA
authors.lastname: Felder
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ohsaki
authors.forename: Kazi
authors.initials: K
authors.lastname: Rafiq
authors.forename: Shamshad J
authors.initials: SJ
authors.lastname: Sherajee
authors.forename: Takahisa
authors.initials: T
authors.lastname: Noma
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakano
mesh_terms: D000118:Acetylglucosaminidase / Q000652:urine; D000450:Aldosterone / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D000077545:Eplerenone; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced; D007668:Kidney / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000235:genetics; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D016159:Tumor Suppressor Protein p53; D006830:Hydralazine; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D000118:Acetylglucosaminidase; D056564:Sirtuin 1