Pharmacological Activation of Sirt1 Ameliorates Cisplatin-Induced Acute Kidney Injury by Suppressing Apoptosis, Oxidative Stress, and Inflammation in Mice
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 effe...
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MDPI AG
2019-08-01
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| Saila: | Antioxidants |
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| Sarrera elektronikoa: | https://www.mdpi.com/2076-3921/8/8/322 |
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| author | Jung-Yeon Kim Jungmin Jo Kiryeong Kim Hyun-Jin An Mi-Gyeong Gwon Hyemin Gu Hyun-Ju Kim A Young Yang Sung-Woo Kim Eon Ju Jeon Jae-Hyung Park Jaechan Leem Kwan-Kyu Park |
| author_facet | Jung-Yeon Kim Jungmin Jo Kiryeong Kim Hyun-Jin An Mi-Gyeong Gwon Hyemin Gu Hyun-Ju Kim A Young Yang Sung-Woo Kim Eon Ju Jeon Jae-Hyung Park Jaechan Leem Kwan-Kyu Park |
| author_sort | Jung-Yeon Kim |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T05:45:08Z |
| format | Article |
| id | doaj.art-1f298a07d12c475a9a5497688459d1f2 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-12T05:45:08Z |
| publishDate | 2019-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-1f298a07d12c475a9a5497688459d1f22023-09-03T05:37:59ZengMDPI AGAntioxidants2076-39212019-08-018832210.3390/antiox8080322antiox8080322Pharmacological Activation of Sirt1 Ameliorates Cisplatin-Induced Acute Kidney Injury by Suppressing Apoptosis, Oxidative Stress, and Inflammation in MiceJung-Yeon Kim0Jungmin Jo1Kiryeong Kim2Hyun-Jin An3Mi-Gyeong Gwon4Hyemin Gu5Hyun-Ju Kim6A Young Yang7Sung-Woo Kim8Eon Ju Jeon9Jae-Hyung Park10Jaechan Leem11Kwan-Kyu Park12Department of Immunology, School of Medicine, Catholic University of Daegu, Daegu 42472, KoreaDepartment of Hematology-Oncology, Inje University Seoul Paik Hospital, Seoul 04551, KoreaDepartment of Physiology, School of Medicine, Keimyung University, Daegu 42601, KoreaDepartment of Pathology, School of Medicine, Catholic University of Daegu, Daegu 42472, KoreaDepartment of Pathology, School of Medicine, Catholic University of Daegu, Daegu 42472, KoreaDepartment of Pathology, School of Medicine, Catholic University of Daegu, Daegu 42472, KoreaDepartment of Pathology, School of Medicine, Catholic University of Daegu, Daegu 42472, KoreaDepartment of Immunology, School of Medicine, Catholic University of Daegu, Daegu 42472, KoreaDepartment of Internal Medicine, School of Medicine, Catholic University of Daegu, Daegu 42472, KoreaDepartment of Internal Medicine, School of Medicine, Catholic University of Daegu, Daegu 42472, KoreaDepartment of Physiology, School of Medicine, Keimyung University, Daegu 42601, KoreaDepartment of Immunology, School of Medicine, Catholic University of Daegu, Daegu 42472, KoreaDepartment of Pathology, School of Medicine, Catholic University of Daegu, Daegu 42472, KoreaSirtuin 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.https://www.mdpi.com/2076-3921/8/8/322sirtuin 1SRT1720cisplatinacute kidney injuryapoptosisoxidative stressinflammation |
| spellingShingle | Jung-Yeon Kim Jungmin Jo Kiryeong Kim Hyun-Jin An Mi-Gyeong Gwon Hyemin Gu Hyun-Ju Kim A Young Yang Sung-Woo Kim Eon Ju Jeon Jae-Hyung Park Jaechan Leem Kwan-Kyu Park Pharmacological Activation of Sirt1 Ameliorates Cisplatin-Induced Acute Kidney Injury by Suppressing Apoptosis, Oxidative Stress, and Inflammation in Mice Antioxidants sirtuin 1 SRT1720 cisplatin acute kidney injury apoptosis oxidative stress inflammation |
| title | Pharmacological Activation of Sirt1 Ameliorates Cisplatin-Induced Acute Kidney Injury by Suppressing Apoptosis, Oxidative Stress, and Inflammation in Mice |
| title_full | Pharmacological Activation of Sirt1 Ameliorates Cisplatin-Induced Acute Kidney Injury by Suppressing Apoptosis, Oxidative Stress, and Inflammation in Mice |
| title_fullStr | Pharmacological Activation of Sirt1 Ameliorates Cisplatin-Induced Acute Kidney Injury by Suppressing Apoptosis, Oxidative Stress, and Inflammation in Mice |
| title_full_unstemmed | Pharmacological Activation of Sirt1 Ameliorates Cisplatin-Induced Acute Kidney Injury by Suppressing Apoptosis, Oxidative Stress, and Inflammation in Mice |
| title_short | Pharmacological Activation of Sirt1 Ameliorates Cisplatin-Induced Acute Kidney Injury by Suppressing Apoptosis, Oxidative Stress, and Inflammation in Mice |
| title_sort | pharmacological activation of sirt1 ameliorates cisplatin induced acute kidney injury by suppressing apoptosis oxidative stress and inflammation in mice |
| topic | sirtuin 1 SRT1720 cisplatin acute kidney injury apoptosis oxidative stress inflammation |
| url | https://www.mdpi.com/2076-3921/8/8/322 |
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