Peroxiredoxin 6 attenuates ischemia‑ and hypoxia‑induced liver damage of brain‑dead donors

Tu,Qiang; Xiong,Yan; Fan,Lin; Qiao,Bingbing; Xia,Zhiping; Hu,Long; Wang,Yanfeng; Peng,Guizhu; Ye,Qifa

doi:10.3892/mmr.2015.4587

Peroxiredoxin 6 attenuates ischemia‑ and hypoxia‑induced liver damage of brain‑dead donors

Authors:
- Qiang Tu
- Yan Xiong
- Lin Fan
- Bingbing Qiao
- Zhiping Xia
- Long Hu
- Yanfeng Wang
- Guizhu Peng
- Qifa Ye
View Affiliations

Affiliations: Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
Published online on: November 19, 2015 https://doi.org/10.3892/mmr.2015.4587
Pages: 753-761
Copyright: © Tu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Oxidative stress induced by ischemia and hypoxia in the livers of donors after brain death (DBD) is associated with poor organ function and low patient survival rates in those receiving DBD liver transplants. Peroxiredoxin 6 (Prdx6) can defend cells against liver damage induced by oxidative stress. The present study aimed to investigate the role of Prdx6 in ischemia‑ and hypoxia‑induced liver damage in DBD livers. Liver tissue samples from ten DBD patients were collected. The control group constituted of six liver samples from patients with liver hemangioma that had accepted tumor excision surgery. Protein expression levels were determined by western blotting, cell viability was assessed using a CCK‑8 assay, intracellular reactive oxygen species (ROS) levels were measured using a ROS assay kit, and phospholipase A2 (PLA2) activity was measured using a PLA2 assay kit. In DBD liver samples, Prdx6 expression was downregulated and the nuclear factor‑κB (NF‑κB) signaling pathway was activated. Furthermore, when human liver L02 cells were exposed to ischemia and hypoxia, the expression of Prdx6 was reduced, causing an increase in reactive oxygen species (ROS); this in turn activated NF‑κB signaling and lowered cell viability (P<0.01). In agreement, overexpression of Prdx6 reduced ROS levels and improved cell viability. It was also demonstrated that inhibition of NF‑κB increased Prdx6 expression, while inhibition of Prdx6 limited PLA2 activity, exacerbating ischemia‑ and hypoxia‑induced cell damage. This data suggests that Prdx6 and its PLA2 activity have a protective role in DBD livers, the expression of which is regulated by NF‑κB. Thus, Prdx6 may be a novel target to alleviate liver damage in DBD.

View Figures

View References

1	Telles-Correia D and Mega I: Candidates for liver transplantation with alcoholic liver disease: Psychosocial aspects. World J Gastroenterol. 21:11027–11033. 2015. View Article : Google Scholar : PubMed/NCBI
2	Heimbach JK, Hirose R, Stock PG, Schladt DP, Xiong H, Liu J, Olthoff KM, Harper A, Snyder JJ, Israni AK, et al: Delayed hepatocellular carcinoma model for end-stage liver disease exception score improves disparity in access to liver transplant in the United States. Hepatology. 61:1643–1650. 2015. View Article : Google Scholar : PubMed/NCBI
3	Park SJ, Lim YS, Hwang S, Heo NY, Lee HC, Suh DJ, Yu E and Lee SG: Emergency adult-to-adult living-donor liver transplantation for acute liver failure in a hepatitis B virus endemic area. Hepatology. 51:903–911. 2010.
4	Huang JF, Wang HB, Zheng SS, Liu YF, Shi BY, Shen ZY, Hu SS, Ye QF, Xue WJ and He XS: Advances in China's organ transplantation achieved with the guidance of law. Chin Med J (Engl). 128:143–146. 2015. View Article : Google Scholar
5	Weiss S, Kotsch K, Francuski M, Reutzel-Selke A, Mantouvalou L, Klemz R, Kuecuek O, Jonas S, Wesslau C, Ulrich F, et al: Brain death activates donor organs and is associated with a worse I/R injury after liver transplantation. Am J Transplant. 7:1584–1593. 2007. View Article : Google Scholar : PubMed/NCBI
6	Barklin A, Larsson A, Vestergaard C, Koefoed-Nielsen J, Bach A, Nyboe R, Wogensen L and Tønnesen E: Does brain death induce a pro-inflammatory response at the organ level in a porcine model? Acta Anaesthesiol Scand. 52:621–627. 2008. View Article : Google Scholar : PubMed/NCBI
7	Kusaka M, Pratschke J, Wilhelm MJ, Ziai F, Zandi-Nejad K, Mackenzie HS, Hancock WW and Tilney NL: Activation of inflammatory mediators in rat renal isografts by donor brain death. Transplantation. 69:405–410. 2000. View Article : Google Scholar : PubMed/NCBI
8	Takada M, Nadeau KC, Hancock WW, Mackenzie HS, Shaw GD, Waaga AM, Chandraker A, Sayegh MH and Tilney NL: Effects of explosive brain death on cytokine activation of peripheral organs in the rat. Transplantation. 5:1533–1542. 1998. View Article : Google Scholar
9	Van Der Hoeven JA, Moshage H, Schuurs T, Nijboer M, Van Schilfgaarde R and Ploeg RJ: Brain death induces apoptosis in donor liver of the rat. Transplantation. 76:1150–1154. 2003. View Article : Google Scholar : PubMed/NCBI
10	Adrie C, Monchi M, Fulgencio JP, Cottias P, Haouache H, Alvarez-Gonzalvez A, Guerrini P, Cavaillon JM and Adib-Conquy M: Immune status and apoptosis activation during brain death. Shock. 33:353–362. 2010. View Article : Google Scholar : PubMed/NCBI
11	Golling M, Mehrabi A, Blum K, Jahnke C, Kellner H, Bud O, Hashemi B, Breitkreutz R, Becker-Brandenbutg K, Schemmer P, et al: Effects of hemodynamic instability on brain death-induced prepreservation liver damage. Transplantation. 75:1154–1159. 2003. View Article : Google Scholar : PubMed/NCBI
12	Dutkiewicz G, Domanski L, Binczak-Kuleta A, Pawlik A, Safranow K, Dziedziejko V, Wisniewska M, Ciechanowicz A and Ciechanowski K: Lack of association of polymorphisms 239+34A/C in the SOD1 gene and 47C/T in the SOD2 gene with delayed graft function and acute and chronic rejection of kidney allografts. Transplant Proc. 41:3701–3703. 2009. View Article : Google Scholar : PubMed/NCBI
13	Rhee SG, Kang SW, Chang TS, Jeong W and Kim K: Peroxiredoxin, a novel family of peroxidases. IUBMB Life. 52:35–41. 2001. View Article : Google Scholar
14	Fisher AB: Peroxiredoxin 6: A bifunctional enzyme with glutathione peroxidase and phospholipase A₂ activities. Antioxid Redox Signal. 15:831–844. 2011. View Article : Google Scholar :
15	Simeone M and Phelan SA: Transcripts associated with Prdx6 (peroxiredoxin 6) and related genes in mouse. Mamm Genome. 16:103–111. 2005. View Article : Google Scholar : PubMed/NCBI
16	Eismann T, Huber N Shin T, Kuboki S, Galloway E, Wyder M, Edwards MJ, Greis KD, Shertzer HG, Fisher AB and Lentsch AB: Peroxiredoxin-6 protects against mitochondrial dysfunction and liver injury during ischemia-reperfusion in mice. Am J Physiol Gastrointest Liver Physiol. 296:G266–G274. 2009. View Article : Google Scholar :
17	Fisher AB, Dodia C, Feinstein SI and Ho YS: Altered lung phospholipid metabolism in mice with targeted deletion of lysosomal-type phospholipase A2. J Lipid Res. 46:1248–1256. 2005. View Article : Google Scholar : PubMed/NCBI
18	Ambruso DR, Ellison MA, Thurman GW and Leto TL: Peroxiredoxin 6 translocates to the plasma membrane during neutrophil activation and is required for optimal NADPH oxidase activity. Biochim Biophys Acta. 1823.306–315. 2012.
19	Lien YC, Feinstein SI, Dodia C and Fisher AB: The roles of peroxidase and phospholipase A2 activities of peroxiredoxin 6 in protecting pulmonary microvascular endothelial cells against peroxidative stress. Antioxid Redox Signal. 16:440–451. 2012. View Article : Google Scholar :
20	Chhunchha B, Fatma N, Kubo E, Rai P, Singh SP and Singh DP: Curcumin abates hypoxia-induced oxidative stress based-ER stress-mediated cell death in mouse hippocampal cells (HT22) by controlling Prdx6 and NF-κB regulation. Am J Physiol Cell Physiol. 304:C636–C655. 2013. View Article : Google Scholar : PubMed/NCBI
21	Chowdhury I, Fisher AB, Christofidou-Solomidou M, Gao L, Tao JQ, Sorokina EM, Lien YC, Bates SR and Feinstein SI: Keratinocyte growth factor and glucocorticoid induction of human peroxiredoxin 6 gene expression occur by independent mechanisms that are synergistic. Antioxid Redox Signal. 20:391–402. 2014. View Article : Google Scholar :
22	Paula FM, Ferreira SM, Boschero AC and Souza KL: Modulation of the peroxiredoxin system by cytokines in insulin-producing RINm5F cells: Down-regulation of PRDX6 increases susceptibility of beta cells to oxidative stress. Mol Cell Endocrinol. 374:56–64. 2013. View Article : Google Scholar : PubMed/NCBI
23	Chen K, Li YH, Xu SQ, Hu SH and Zhang L: Protective effects of peroxisome proliferator-activated receptor-α agonist, Wy14643, on hypoxia/reoxygenation injury in primary rat hepatocytes. PPAR Res. 2012:5479802012. View Article : Google Scholar
24	Chhunchha B, Fatma N, Bhargavan B, Kubo E, Kumar A and Singh DP: Specificity protein, Sp1-mediated increased expression of Prdx6 as a curcumin-induced antioxidant defense in lens epithelial cells against oxidative stress. Cell Death Dis. 2:e2342011. View Article : Google Scholar : PubMed/NCBI
25	Gallagher BM and Phelan SA: Investigating transcriptional regulation of Prdx6 in mouse liver cells. Free Radic Biol Med. 42:1270–1277. 2007. View Article : Google Scholar : PubMed/NCBI
26	Tulsawani R, Kelly LS, Fatma N, Chhunchha B, Kubo E, Kumar A and Singh DP: Neuroprotective effect of peroxiredoxin 6 against hypoxia-induced retinal ganglion cell damage. BMC Neurosci. 11:1252010. View Article : Google Scholar : PubMed/NCBI
27	Wang Y, Xu Y, Wang H, Xue P, Li X, Li B, Zheng Q and Sun G: Arsenic induces mitochondria-dependent apoptosis by reactive oxygen species generation rather than glutathione depletion in Chang human hepatocytes. Arch Toxicol. 83:899–908. 2009. View Article : Google Scholar : PubMed/NCBI
28	Fatma N, Kubo E, Sen M, Agarwal N, Thoreson WB, Camras CB and Singh DP: Peroxiredoxin 6 delivery attenuates TNF-alpha-and glutamate-induced retinal ganglion cell death by limiting ROS levels and maintaining Ca²⁺ homeostasis. Brain Res. 1233:63–78. 2008. View Article : Google Scholar : PubMed/NCBI
29	Sun XG, Fu XQ, Cai HB, Liu Q, Li CH, Liu YW, Li YJ, Liu ZF, Song YH and Lv ZP: Proteomic analysis of protective effects of polysaccharides from Salvia miltiorrhiza against immunological liver injury in mice. Phytother Res. 25:1087–1094. 2011. View Article : Google Scholar : PubMed/NCBI
30	Roede JR, Stewart BJ and Petersen DR: Decreased expression of peroxiredoxin 6 in a mouse model of ethanol consumption. Free Radic Biol Med. 45:1551–1558. 2008. View Article : Google Scholar : PubMed/NCBI
31	Gloire G, Legrand-Poels S and Piette J: NF-kappaB activation by reactive oxygen species: Fifteen years later. Biochem Pharmacol. 72:1493–1505. 2006. View Article : Google Scholar : PubMed/NCBI
32	Zhang H, Wang ZW, Wu HB, Li Z, Li LC, Hu XP, Ren ZL, Li BJ and Hu ZP: Transforming growth factor-β1 induces matrix metal-loproteinase-9 expression in rat vascular smooth muscle cells via ROS-dependent ERK-NF-κB pathways. Mol Cell Biochem. 375:11–21. 2013.PubMed/NCBI
33	Girotti AW: Lipid hydroperoxide generation, turnover, and effector action in biological systems. J Lipid Res. 39:1529–1542. 1998.PubMed/NCBI
34	Schaloske RH and Dennis EA: The phospholipase A2 superfamily and its group numbering system. Biochim Biophys Acta. 1761:1246–1259. 2006. View Article : Google Scholar : PubMed/NCBI
35	Winstead MV, Balsinde J and Dennis EA: Calcium-independent phospholipase A(2): Structure and function. Biochim Biophys Acta. 1488:28–39. 2000. View Article : Google Scholar : PubMed/NCBI
36	Manevich Y, Shuvaeva T, Dodia C, Kazi A, Feinstein SI and Fisher AB: Binding of peroxiredoxin 6 to substrate determines differential phospholipid hydroperoxide peroxidase and phospholipase A(2) activities. Arch Biochem Biophys. 485:139–149. 2009. View Article : Google Scholar : PubMed/NCBI