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Sirtuin-1 attenuates cadmium-induced renal cell senescence through p53 deacetylation

Xin Chou¹, Xiaohu Li², Zhen Min³

¹Department of Occupational Disease, Shanghai Pulmonary Hospital affiliated Tongji University, 507 Zhengmin road, Shanghai 200433, China; School of Public Health, Fudan University, 130 Dong'An Road, Shanghai 200032, China.

Ecotoxicology and Environmental Safety

|September 22, 2022

Abstract:

Cadmium (Cd), the common environmental pollutant, primarily targets at renal proximal tubules and induces nephrotoxicity. Cellular senescence, a phenomenon of cell growth arrest and a characteristics of maladaptive cell self-repair, is associated with renal disease progression. However, whether and how Cd induces renal tubular cells premature senescence is unknown. In our study, we found that Cd induced kidney damage and dysfunctions, which correlated with exacerbated tubular cell senescence, evidenced by increased senescence-associated β-galactosidase activity, the upregulated protein expression of p53 and p21^Waf1/Cip1 proteins, and elevated expression and secretion of cytokines in human proximal tubular epithelial HK-2 cells in vitro and in Cd-treated mice in vivo. Moreover, a S-phase arrest and decrease in Edu positive rate were found in Cd-treated HK-2 cells. Mechanistically, Cd suppressed the expression and activity of Sirtuin-1 (SIRT1), an anti-senescence deacetylase, resulting in the accumulation of acetylated p53 and upregulation of p21^Waf1/Cip1. Activation of SIRT1 significantly abolished Cd-induced premature senescence and S-phase arrest. Finally, silencing p21^Waf1/Cip1 efficiently delayed premature senescence and recovered cell cycle progression. These findings indicate that Cd promotes tubular cells senescence and impairs tubular cells regeneration, resulting in kidney dysfunctions, which could be ameliorated by SIRT1 activation.

Insights

Cadmium exposure causes premature kidney tubular cell senescence by inhibiting Sirtuin-1 (SIRT1), leading to kidney dysfunction. Activating SIRT1 or silencing p21 may protect against cadmium-induced nephrotoxicity.

Area of Science:

Environmental toxicology
Nephrology
Cellular biology

Background:

Cadmium (Cd) is an environmental pollutant causing kidney damage.
Cellular senescence is linked to kidney disease progression.
The role of Cd in inducing premature renal tubular cell senescence remains unclear.

Purpose of the Study:

To investigate if and how cadmium induces premature senescence in renal tubular cells.
To elucidate the underlying molecular mechanisms.
To explore potential therapeutic targets for cadmium-induced nephrotoxicity.

Main Methods:

In vitro studies using human proximal tubular epithelial HK-2 cells.
In vivo studies using Cd-treated mice.
Assessed senescence markers (β-galactosidase, p53, p21^Waf1/Cip1).
Investigated cell cycle progression (Edu incorporation) and Sirtuin-1 (SIRT1) activity.
Utilized SIRT1 activation and p21^Waf1/Cip1 silencing.

Main Results:

Cd exposure induced kidney damage and dysfunction in mice.
Cd treatment increased senescence markers and cytokines in HK-2 cells and mice.
Cd caused S-phase arrest and reduced proliferation in HK-2 cells.
Cd suppressed SIRT1 expression and activity, leading to p53 acetylation and p21^Waf1/Cip1 upregulation.
SIRT1 activation ameliorated Cd-induced senescence and cell cycle arrest.
p21^Waf1/Cip1 silencing delayed senescence and restored cell cycle progression.

Conclusions:

Cadmium promotes premature senescence in renal tubular cells via SIRT1 inhibition and p21^Waf1/Cip1 upregulation.
This senescence contributes to cadmium-induced kidney dysfunction and impaired regeneration.
SIRT1 activation represents a potential therapeutic strategy against cadmium nephrotoxicity.

Read full analysis

Keywords:

Cd Cell premature senescence Proximal tubular epithelial cell SIRT1

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