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.

The proximal tubular renin–angiotensin system during albuminuria

“…These findings are in agreement with those of previous reports in which an increase in albuminuria was found to be associated with an augmentation of the intrarenal RAS and tubulointerstitial fibrosis [14][15][16][17][18][19]. Taken together, these findings may help in our understanding of the potential role of albumin-induced PTC stress in the progression of renal injury.…”

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

“…MR activation is associated with cellular aging in the kidney, with the induction of senescence-associated b galactosidase, of the cyclin-dependent kinase inhibitor (p21) and decreased expression of SIRT1 (Fan et al, 2011). In VSMC, aldosterone stimulates senescence and p21, p53, P16, p27, and Ki-ras2 expression (Min et al, 2007).…”

Matrix metalloproteinase 2 induces epithelial-mesenchymal transition in proximal tubules from the luminal side and progresses fibrosis in mineralocorticoid/salt-induced hypertensive rats

“…These currently unresolved issues need further investigation, including in-vitro experiments on cultured proximal tubule cells. Fourth, although our current study revealed that proximal tubule cells are a target of the deleterious effects of DOCA, we did not examine the expression of mineralocorticoid receptor in proximal tubule cells in the three groups of rats, even though several studies have reported that cultured human proximal tubule cells express mineralocorticoid receptor [45,46]. Finally, we did not evaluate whether proximal tubule cell tight junction surface proteins other than claudin 2, including claudin 10 [31,42], were also downregulated in the DOCA group at weeks 4 and 8.…”