Abstract
Sirtuin 1 (Sirt1) is an essential modulator of cellular metabolism and has pleiotropic effects. It was recently reported that Sirt1 overexpression in kidney tubule ameliorates cisplatin-induced acute kidney injury (AKI). However, whether pharmacological activation of Sirt1 also has a beneficial effect against the disease remains unclear. In this study, we aimed to evaluate whether SRT1720, a potent and specific activator of Sirt1, could ameliorate cisplatin-induced AKI. We found that SRT1720 treatment ameliorated cisplatin-induced acute renal failure and histopathological alterations. Increased levels of tubular injury markers in kidneys were significantly attenuated by SRT1720. SRT1720 treatment also suppressed caspase-3 activation and apoptotic cell death. Increased expression of 4-hydroxynonenal, elevated malondialdehyde level, and decreased ratio of reduced glutathione/oxidized glutathione after cisplatin injection were significantly reversed by SRT1720. In addition, SRT1720 treatment decreased renal expression of pro-inflammatory cytokines and prevented macrophage infiltration into damaged kidneys. We also showed that the therapeutic effects of SRT1720 were associated with reduced acetylation of p53 and nuclear factor kappa-B p65 and preservation of peroxisome function, as evidenced by recovered expression of markers for number and function of peroxisome. These results suggest that Sirt1 activation by SRT1720 would be a useful therapeutic option for cisplatin-induced AKI.
Highlights
Cisplatin is a chemotherapy drug used for the treatment of many different types of cancer, including ovarian, testicular, bladder, and lung cancer [1,2,3]
We found that mice treated with cisplatin alone exhibited a dramatic reduction in mRNA expression of PEX14 and catalase compared to control mice and these changes were largely reversed by SRT1720 (Figure 7A,B)
Administration of SRT1720 significantly reduced the protein level of acetylated p65 in kidneys of mice treated with cisplatin. These findings suggest that Sirtuin 1 (Sirt1) activation of SRT1720 inhibits NF-κB, probably by deacetylating p65 subunit
Summary
Cisplatin is a chemotherapy drug used for the treatment of many different types of cancer, including ovarian, testicular, bladder, and lung cancer [1,2,3]. Some strategies including intensive hydration have been used, there is no satisfactory treatment to protect against cisplatin-induced AKI. Numerous studies suggest that Sirt is mainly responsible for modulation of energy. Sirt is known to inhibit cell apoptosis, inflammatory responses, and oxidative stress through deacetylating a variety of substrates including p53 [6,7] and p65 subunit of nuclear factor kappa-B (NF-κB) [8,9]. Sirt has been recognized as a useful therapeutic target for the therapy of numerous inflammatory diseases. It was shown that Sirt overexpression in kidney tubules ameliorates cisplatin-induced AKI by inhibiting apoptotic cell death and oxidative stress [10]. Whether pharmacological activation of Sirt has a beneficial effect against cisplatin-induced AKI has not yet been fully determined
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