Absence of Sirt3 aggravates cisplatin nephrotoxicity via enhanced renal tubular apoptosis and inflammation

Kim,Dal; Park,Woong; Lee,Sik; Kim,Won; Park,Sung  Kwang; Kang,Kyung  Pyo

doi:10.3892/mmr.2018.9350

Absence of Sirt3 aggravates cisplatin nephrotoxicity via enhanced renal tubular apoptosis and inflammation

Authors:
- Dal Kim
- Woong Park
- Sik Lee
- Won Kim
- Sung Kwang Park
- Kyung Pyo Kang
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Affiliations: Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Jeollabuk‑do 54907, Republic of Korea
Published online on: August 3, 2018 https://doi.org/10.3892/mmr.2018.9350
Pages: 3665-3672
Copyright: © Kim et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Cisplatin‑based chemotherapy is commonly used in the treatment of solid tumors; however, this agent is limited by its adverse effects on normal tissues, including the kidneys, ears and peripheral nerves. Mechanisms of cisplatin nephrotoxicity are proposed to involve oxidative stress, inflammation, cellular apoptosis and cell cycle regulation. Sirtuin 3 (Sirt3) is a member of the sirtuin family of NAD+‑dependent enzymes with homology to Saccharomyces cerevisiae gene silent information regulator 2. Sirt3 is located in mitochondria and is involved in mitochondrial energy metabolism and function; however, the role of Sirt3 in cisplatin nephrotoxicity remains unclear. In the present study, whether Sirt3 has anti‑inflammatory and anti‑apoptotic effects on cisplatin‑induced nephrotoxicity was investigated in mice. Sirt3 knockout mice (Sirt3(‑/‑)) and corresponding wild type mice were employed in the present study. Cisplatin nephrotoxicity was induced by intraperitoneal injection of cisplatin (20 mg/kg). After 3 days following cisplatin treatment, blood and kidney tissues were harvested. Renal function and histology were evaluated. Tubular apoptosis, cell adhesion molecule expression, and inflammatory cells were evaluated by immunohistochemistry and western blot analysis. Following the induction of cisplatin nephrotoxicity, renal function was significantly aggravated in Sirt3 knockout (KO) mice. Tubular injury and inflammatory cell infiltration were significantly increased in Sirt3KO mice compared with wild type mice. Terminal deoxynucleotidyl transferase‑mediated dUTP nick‑end label‑positive tubular cells and renal monocyte chemoattractant protein‑1 expression levels were increased in Sirt3KO mice compared with in wild type mice. In summary, the absence of Sirt3 aggravated in renal injury by increasing renal inflammation and tubular apoptosis. The results of the present study suggested that Sirt3 may have an important role in cisplatin‑induced nephrotoxicity.

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1	dos Santos NA, Carvalho Rodrigues MA, Martins NM and dos Santos AC: Cisplatin-induced nephrotoxicity and targets of nephroprotection: An update. Arch Toxicol. 86:1233–1250. 2012. View Article : Google Scholar : PubMed/NCBI
2	Arany I and Safirstein RL: Cisplatin nephrotoxicity. Semin Nephrol. 23:460–464. 2003. View Article : Google Scholar : PubMed/NCBI
3	Perazella MA and Moeckel GW: Nephrotoxicity from chemotherapeutic agents: Clinical manifestations, pathobiology, and prevention/therapy. Semin Nephrol. 30:570–581. 2010. View Article : Google Scholar : PubMed/NCBI
4	Launay-Vacher V, Rey JB, Isnard-Bagnis C, Deray G and Daouphars M: European Society of Clinical Pharmacy Special Interest Group on Cancer Care: Prevention of cisplatin nephrotoxicity: State of the art and recommendations from the European society of clinical pharmacy special interest group on cancer care. Cancer Chemother Pharmacol. 61:903–909. 2008. View Article : Google Scholar : PubMed/NCBI
5	Bause AS and Haigis MC: SIRT3 regulation of mitochondrial oxidative stress. Exp Gerontol. 48:634–639. 2013. View Article : Google Scholar : PubMed/NCBI
6	Haigis MC and Guarente LP: Mammalian sirtuins-emerging roles in physiology, aging, and calorie restriction. Genes Dev. 20:2913–2921. 2006. View Article : Google Scholar : PubMed/NCBI
7	Sack MN: The role of SIRT3 in mitochondrial homeostasis and cardiac adaptation to hypertrophy and aging. J Mol Cell Cardiol. 52:520–525. 2012. View Article : Google Scholar : PubMed/NCBI
8	Lombard DB, Alt FW, Cheng HL, Bunkenborg J, Streeper RS, Mostoslavsky R, Kim J, Yancopoulos G, Valenzuela D, Murphy A, et al: Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol Cell Biol. 27:8807–8814. 2007. View Article : Google Scholar : PubMed/NCBI
9	Dang W: The controversial world of sirtuins. Drug Discov Today Technol. 12:e9–e17. 2014. View Article : Google Scholar : PubMed/NCBI
10	Ahn BH, Kim HS, Song S, Lee IH, Liu J, Vassilopoulos A, Deng CX and Finkel T: A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci USA. 105:pp. 14447–14452. 2008; View Article : Google Scholar : PubMed/NCBI
11	Qiu X, Brown K, Hirschey MD, Verdin E and Chen D: Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab. 12:662–667. 2010. View Article : Google Scholar : PubMed/NCBI
12	Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, Grueter CA, Harris C, Biddinger S, Ilkayeva OR, et al: SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature. 464:121–125. 2010. View Article : Google Scholar : PubMed/NCBI
13	Bellizzi D, Rose G, Cavalcante P, Covello G, Dato S, De Rango F, Greco V, Maggiolini M, Feraco E, Mari V, Franceschi C, et al: A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages. Genomics. 85:258–263. 2005. View Article : Google Scholar : PubMed/NCBI
14	Koentges C, Bode C and Bugger H: SIRT3 in cardiac physiology and Disease. Front Cardiovasc Med. 3:382016. View Article : Google Scholar : PubMed/NCBI
15	Zeng H, Vaka VR, He X, Booz GW and Chen JX: High-fat diet induces cardiac remodelling and dysfunction: Assessment of the role played by SIRT3 loss. J Cell Mol Med. 19:1847–1856. 2015. View Article : Google Scholar : PubMed/NCBI
16	Zeng H, He X, Hou X, Li L and Chen JX: Apelin gene therapy increases myocardial vascular density and ameliorates diabetic cardiomyopathy via upregulation of sirtuin 3. American journal of physiology. Am J Physiol Heart Circ Physiol. 306:H585–H597. 2014. View Article : Google Scholar : PubMed/NCBI
17	Allison SJ and Milner J: SIRT3 is pro-apoptotic and participates in distinct basal apoptotic pathways. Cell Cycle. 6:2669–2677. 2007. View Article : Google Scholar : PubMed/NCBI
18	Jiao X, Li Y, Zhang T, Liu M and Chi Y: Role of Sirtuin3 in high glucose-induced apoptosis in renal tubular epithelial cells. Biochem Biophys Res Commun. 480:387–393. 2016. View Article : Google Scholar : PubMed/NCBI
19	Koyama T, Kume S, Koya D, Araki S, Isshiki K, Chin-Kanasaki M, Sugimoto T, Haneda M, Sugaya T, Kashiwagi A, et al: SIRT3 attenuates palmitate-induced ROS production and inflammation in proximal tubular cells. Free Radic Biol Med. 51:1258–1267. 2011. View Article : Google Scholar : PubMed/NCBI
20	Ramesh G and Reeves WB: TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J Clin Invest. 110:835–842. 2002. View Article : Google Scholar : PubMed/NCBI
21	Kang KP, Park SK, Kim DH, Sung MJ, Jung YJ, Lee AS, Lee JE, Ramkumar KM, Lee S, Park MH, et al: Luteolin ameliorates cisplatin-induced acute kidney injury in mice by regulation of p53-dependent renal tubular apoptosis. Nephrol Dial Transplant. 26:814–822. 2011. View Article : Google Scholar : PubMed/NCBI
22	Kang KP, Kim DH, Jung YJ, Lee AS, Lee S, Lee SY, Jang KY, Sung MJ, Park SK and Kim W: Alpha-lipoic acid attenuates cisplatin-induced acute kidney injury in mice by suppressing renal inflammation. Nephrol Dial Transplant. 24:3012–3020. 2009. View Article : Google Scholar : PubMed/NCBI
23	Jung YJ, Lee JE, Lee AS, Kang KP, Lee S, Park SK, Lee SY, Han MK, Kim DH and Kim W: SIRT1 overexpression decreases cisplatin-induced acetylation of NF-κB p65 subunit and cytotoxicity in renal proximal tubule cells. Biochem Biophys Res Commun. 419:206–210. 2012. View Article : Google Scholar : PubMed/NCBI
24	Kim DH, Jung YJ, Lee JE, Lee AS, Kang KP, Lee S, Park SK, Han MK, Lee SY, Ramkumar KM, et al: SIRT1 activation by resveratrol ameliorates cisplatin-induced renal injury through deacetylation of p53. Am J Physiol Renal Physiol. 301:F427–F435. 2011. View Article : Google Scholar : PubMed/NCBI
25	Morigi M, Perico L, Rota C, Longaretti L, Conti S, Rottoli D, Novelli R, Remuzzi G and Benigni A: Sirtuin 3-dependent mitochondrial dynamic improvements protect against acute kidney injury. J Clin Invest. 125:715–726. 2015. View Article : Google Scholar : PubMed/NCBI
26	Kim D, Lee AS, Jung YJ, Yang KH, Lee S, Park SK, Kim W and Kang KP: Tamoxifen ameliorates renal tubulointerstitial fibrosis by modulation of estrogen receptor alpha-mediated transforming growth factor-β1/Smad signaling pathway. Nephrol Dial Transplant. 29:2043–2053. 2014. View Article : Google Scholar : PubMed/NCBI
27	Pabla N and Dong Z: Cisplatin nephrotoxicity: Mechanisms and renoprotective strategies. Kidney Int. 73:994–1007. 2008. View Article : Google Scholar : PubMed/NCBI
28	Havasi A and Borkan SC: Apoptosis and acute kidney injury. Kidney Int. 80:29–40. 2011. View Article : Google Scholar : PubMed/NCBI
29	Fischler R, Meert AP, Sculier JP and Berghmans T: Continuous renal replacement therapy for acute renal failure in patients with cancer: A well-tolerated adjunct treatment. Front Med (Lausanne). 3:332016.PubMed/NCBI
30	Sung MJ, Kim DH, Jung YJ, Kang KP, Lee AS, Lee S, Kim W, Davaatseren M, Hwang JT, Kim HJ, et al: Genistein protects the kidney from cisplatin-induced injury. Kidney Int. 74:1538–1547. 2008. View Article : Google Scholar : PubMed/NCBI
31	Park MS, De Leon M and Devarajan P: Cisplatin induces apoptosis in LLC-PK1 cells via activation of mitochondrial pathways. J Am Soc Nephrol. 13:858–865. 2002.PubMed/NCBI
32	Perico L, Morigi M and Benigni A: Mitochondrial Sirtuin 3 and Renal Diseases. Nephron. 134:14–19. 2016. View Article : Google Scholar : PubMed/NCBI
33	Marfe G, Tafani M, Indelicato M, Sinibaldi-Salimei P, Reali V, Pucci B, Fini M and Russo MA: Kaempferol induces apoptosis in two different cell lines via Akt inactivation, Bax and SIRT3 activation, and mitochondrial dysfunction. J Cell Biochem. 106:643–650. 2009. View Article : Google Scholar : PubMed/NCBI
34	Sundaresan NR, Samant SA, Pillai VB, Rajamohan SB and Gupta MP: SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Mol Cell Biol. 28:6384–6401. 2008. View Article : Google Scholar : PubMed/NCBI
35	Pillai VB, Samant S, Sundaresan NR, Raghuraman H, Kim G, Bonner MY, Arbiser JL, Walker DI, Jones DP, Gius D and Gupta MP: Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3. Nat Commun. 6:66562015. View Article : Google Scholar : PubMed/NCBI
36	Averett C, Arora S, Zubair H, Singh S, Bhardwaj A and Singh AP: Molecular targets of honokiol: A promising phytochemical for effective cancer management. Enzymes. 36:175–193. 2014. View Article : Google Scholar : PubMed/NCBI
37	Kumar A, Kumar Singh U and Chaudhary A: Honokiol analogs: A novel class of anticancer agents targeting cell signaling pathways and other bioactivities. Future Med Chem. 5:809–829. 2013. View Article : Google Scholar : PubMed/NCBI
38	Zordoky BN, Robertson IM and Dyck JR: Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases. Biochim Biophys Acta. 1852:1155–1177. 2015. View Article : Google Scholar : PubMed/NCBI
39	Chen T, Li J, Liu J, Wang S, Liu H, Zeng M, Zhang Y and Bu P: Activation of SIRT3 by resveratrol ameliorates cardiac fibrosis and improves cardiac function via the TGF-β/Smad3 pathway. Am J Physiol Heart Circ Physiol. 308:H424–H434. 2015. View Article : Google Scholar : PubMed/NCBI
40	Alhazzazi TY, Kamarajan P, Xu Y, Ai T, Chen L, Verdin E and Kapila YL: A Novel Sirtuin-3 Inhibitor, LC-0296, inhibits cell survival and proliferation, and promotes apoptosis of head and neck cancer cells. Anticancer Res. 36:49–60. 2016.PubMed/NCBI