請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/18298
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 劉興華(Shing-Hwa Liu) | |
dc.contributor.author | Bo-Lin Chen | en |
dc.contributor.author | 陳柏霖 | zh_TW |
dc.date.accessioned | 2021-06-08T00:58:39Z | - |
dc.date.copyright | 2015-03-12 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-01-28 | |
dc.identifier.citation | Adachi T, N Sugiyama, H Yagita, T Yokoyama. Renal atrophy after ischemia-reperfusion injury depends on massive tubular apoptosis induced by TNFα in the later phase. Med Mol Morphol 47: 213-23, 2014.
Adachi T, N Sugiyama, T Gondai, H Yagita, and T Yokoyama. Blockade of death ligand TRAIL inhibits renal ischemia reperfusion injury. Acta Histochem Cytochem 46: 161–170, 2013. Adams JM and S Cory. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26: 1324–1337, 2007. Allagnat F, M Fukaya, TC Nogueira, D Delaroche, N Welsh, L Marselli, P Marchetti, JA Haefliger, DL Eizirik, and AK Cardozo. C/EBP homologous protein contributes to cytokine-induced pro-inflammatory responses and apoptosis in beta-cells. Cell Death Differ 19: 1836–1846, 2012. Al-Lamki RS, J Wang, P Vandenabeele, JA Bradley, S Thiru, D Luo, W Min, JS Pober, and JR Bradley. TNFR1- and TNFR2-mediated signaling pathways in human kidney are cell type-specific and differentially contribute to renal injury. FASEB J 19: 1637–1645, 2005. Bando Y, Y Tsukamoto, T Katayama, K Ozawa, Y Kitao, O Hori, DM Stern, A Yamauchi, and S Ogawa. ORP150/HSP12A protects renal tubular epithelium from ischemia-induced cell death. FASEB J 18: 1401–1403, 2004. Beauchamp C and I Fridovich. Superoxide dismutase: improved assays and an assay applicable to acrylamide gels. Anal Biochem 44: 276–287, 1971. Bonventre JV, A Zuk. Ischemic acute renal failure: an inflammatory disease? Kidney Int 66: 480-485, 2004. Carlson SG, TW Fawcett, JD Bartlett, M Bernier, and NJ Holbrook. Regulation of the C/EBP-related gene gadd153 by glucose deprivation. Mol Cell Biol 13: 4736–4744, 1993. Chatterjee PK, BE Chatterjee, H Pedersen, A Sivarajah, MC McDonald, H Mota-Filipe, PA Brown, KN Stewart, S Cuzzocrea, MD Threadgill, and C Thiemermann. 5-Aminoisoquinolinone reduces renal injury and dysfunction caused by experimental ischemia/reperfusion. Kidney Int 65: 499–509, 2004. Chen BL, LT Wang, KH Huang, CC Wang, CK Chiang, SH Liu. Quercetin attenuates renal ischemia/reperfusion injury via an activation of AMP-activated protein kinase-regulated autophagy pathway. J Nutr Biochem 25: 1226-34, 2014. Chen CM, CT Wu, CK Chiang, BW Liao, and SH Liu. C/EBP homologous protein (CHOP) deficiency aggravates hippocampal cell apoptosis and impairs memory performance. PLoS One 7: e40801, 2012. Chen Y, H Gao, Q Yin, L Chen, P Dong, X Zhang, and J Kang. ER stress activating ATF4/CHOP-TNF-α signaling pathway contributes to alcohol-induced disruption of osteogenic lineage of multipotential mesenchymal stem cell. Cell Physiol Biochem 32: 743–754, 2013. Chiang CK, ML Sheu, YW Lin, CT Wu, CC Yang, MW Chen, KY Hung, KD Wu, and SH Liu. Honokiol ameliorates renal fibrosis by inhibiting extracellular matrix and pro-inflammatory factors in vivo and in vitro. Br J Pharmacol 163: 586–597, 2011. Chiang CK, SP Hsu, CT Wu, JW Huang, HT Cheng, YW Chang, KY Hung, KD Wu, and SH Liu. Endoplasmic reticulum stress implicated in the development of renal fibrosis. Mol Med 17: 1295–1305, 2011. Chiao MT, WY Cheng, YC Yang, CC. Shen, JL Ko. Suberoylanilide hydroxamic acid (SAHA) causes tumor growth slowdown and triggers autophagy in glioblastoma stem cells. Autophagy 9: 1509–1526, 2013. Dai R, D Yan, J Li, S Chen, Y Liu, R Chen, C Duan, M Wei, H Li, and T He. Activation of PKR/eIF2α signaling cascade is associated with dihydrotestosterone-induced cell cycle arrest and apoptosis in human liver cells. J Cell Biochem 113: 1800–1808, 2012. Devarajan P Update on mechanisms of ischemic acute kidney injury. J Am Soc Nephrol 17: 1503-20 ,2006. Doi S, T Masaki, T Arakawa, S Takahashi, T Kawai, A Nakashima, T Naito, N Kohno, and N Yorioka. Protective effects of peroxisome proliferator-activated receptor gamma ligand on apoptosis and hepatocyte growth factor induction in renal ischemia-reperfusion injury. Transplantation 84: 207–213, 2007. Dong B, H Zhou, C Han, J Yao, L Xu, M Zhang, Y Fu, Q Xia. Ischemia/reperfusion-induced CHOP expression promotes apoptosis and impairs renal function recovery: the role of acidosis and GPR4. PLoS One 9: e110944, 2014. Droge W. Free radicals in the physiological control of cell function. Physiol Rev 82: 47–95, 2002. Endo M, M Mori, S Akira, and T Gotoh. C/EBP homologous protein (CHOP) is crucial for the induction of caspase-11 and the pathogenesis of lipopolysaccharide-induced inflammation. J Immunol 176: 6245–6253, 2006. Fang F, GC Liu, C Kim, R Yassa, J Zhou, JW. Scholey Adiponectin attenuates angiotensin II-induced oxidative stress in renal tubular cells through AMPK and cAMP-Epac signal transduction pathways. Am J Physiol Renal Physiol 304: F1366–F1374, 2013. Galehdar Z, P Swan, B Fuerth, SM Callaghan, DS Park, and SP Cregan. Neuronal apoptosis induced by endoplasmic reticulum stress is regulated by ATF4-CHOP-mediated induction of the Bcl-2 homology 3-only member PUMA. J Neurosci 30: 16938–16948, 2010. Gang GT, Hwang JH, Kim YH, Noh JR, Kim KS, Jeong JY, Choi DE, Lee KW, Jung JY, Shong M, Lee CH Protecti. .on of NAD(P)H:quinone oxidoreductase 1 against ACSSrenal ischemia/reperfusion injury in mice. Free Radic Biol Med 67: 139-49, 2014. Ghosh S, M Khazaei, F Moien-Afshari, LS Ang, DJ Granville, CB Verchere, SR Dunn, P McCue, A Mizisin, K Sharma, and I Laher. Moderate exercise attenuates caspase-3 activity, oxidative stress, and inhibits progression of diabetic renal disease in db/db mice. Am J Physiol Renal Physiol 296: F700–F708, 2009. Gotoh T, S Oyadomari, K Mori, and M Mori. Nitric oxide-induced apoptosis in RAW 264.7 macrophages is mediated by endoplasmic reticulum stress pathway involving ATF6 and CHOP. J Biol Chem 277: 12343–12350, 2002. Gupta SC, SK Francis, MS Nair, YY Mo, and BB Aggarwal. Azadirone, a limonoid tetranortriterpene, induces death receptors and sensitizes human cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) through a p53 protein-independent mechanism: evidence for the role of the ROS-ERK-CHOP-death receptor pathway. J Biol Chem 288: 32343–32356, 2013. Guo H, H Aleyasin, SS Howard, BC Dickinson, VS Lin, RE Haskew-Layton, C Xu, Y Chen, and RR Ratan. Two-photon fluorescence imaging of intracellular hydrogen peroxide with chemoselective fluorescent probes. J Biomed Opt 18: 106002, 2013. Halliwell B. Free radicals and antioxidants: updating a personal view. Nutr Rev 70: 257–265, 2012. Hardie DG, SA Hawley, JW Scott. AMP-activated protein kinase--development of the energy sensor concept. J Physiol 574: 7-15, 2006. He L, JH Jang, HG Choi, SM Lee, MH Nan, SJ Jeong, Z Dong, YT Kwon, KS Lee, KW Lee, JK Chung, JS Ahn, and BY Kim. Oligomycin A enhances apoptotic effect of TRAIL through CHOP-mediated death receptor 5 expression. Mol Carcinog 52: 85–93, 2013. Holness CL and DL Simmons. Molecular cloning of CD68, a human macrophage marker related to lysosomal glycoproteins. Blood 81: 1607–1613, 1993. Inagi R. Endoplasmic reticulum stress as a progression factor for kidney injury. Curr Opin Pharmacol 10: 156–165, 2010. Inagi R. Endoplasmic reticulum stress in the kidney as a novel mediator of kidney injury. Nephron Exp Nephrol 112: e1–e9, 2009. Inal M, M Altinisik, MD Bilgin. The effect of quercetin on renal ischemia and reperfusion injury in the rat. Cell Biochem Funct 20: 291–296, 2002. Jang HR, H Rabb. Immune cells in experimental acute kidney injury. Nat Rev Nephrol, 2014 [Epub ahead of print]. JaliliT, J Carlstrom, S Kim, D Freeman, H Jin, TC Wu, SE Litwin, J David Symons. Quercetin-supplemented diets lower blood pressure and attenuate cardiac hypertrophy in rats with aortic constriction. J Cardiovasc Pharmacol 47: 531-541, 2006. Javed S, R Mejias-Luque, B Kalali, C Bolz, and M Gerhard. Helicobacter bilis gamma-glutamyltranspeptidase enhances inflammatory stress response via oxidative stress in colon epithelial cells. PLoS One 8: e73160, 2013. Jhun BS, Q Jin, YT Oh, SS Kim, Y Kong, YH Cho, J Ha, HH Baik, I Kang.5-Aminoimidazole-4-carboxamide riboside suppresses lipopolysaccharide-induced TNF-alpha production through inhibition of phosphatidylinositol 3-kinase/Akt activation in RAW 264•7 murine macrophages. Biochem Biophys Res Commun 318: 372–380, 2004. Johansson LH, and LA Borg. A spectrophotometric method for determination of catalase activity in small tissue samples. Anal Biochem 174: 331–336, 1988. Jung KJ, Kim DH, Lee EK, Song CW, Yu BP, and Chung HY. Oxidative stress induces inactivation of protein phosphatase 2A, promoting proinflammatory NF-kappaB in aged rat kidney. Free Radic Biol Med 61: 206–217, 2013. Kahraman A, N Erkasap, M Serteser, T Koken. Protective effect of quercetin on renal ischemia/reperfusion injury in rats. J Nephrol 16: 219–224, 2003. Kawakami T, R Inagi, T Wada, T Tanaka, T Fujita, and M Nangaku. Indoxyl sulfate inhibits proliferation of human proximal tubular cells via endoplasmic reticulum stress. Am J Physiol Renal Physiol 299: F568–F576, 2010. Kelly KJ, Z Plotkin, SL Vulgamott, and PC Dagher. P53 mediates the apoptotic response to GTP depletion after renal ischemia-reperfusion: protective role of a p53 inhibitor. J Am Soc Nephrol 14: 128–138, 2003. Kim GT, SH Lee, YM Kim. Quercetin Regulates Sestrin 2-AMPK-mTOR Signaling Pathway and Induces Apoptosis via Increased Intracellular ROS in HCT116 Colon Cancer Cells. J Cancer Prev 18: 264-270, 2013. Kim I, W Xu, JC Reed. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov 7:1013-1030, 2008. Kim J, JW Park, KM Park. Increased superoxide formation induced by irradiation preconditioning triggers kidney resistance to ischemia–reperfusion injury in mice. Am. J. Physiol. Renal Physiol 296: 1202–1211, 2009. Kohno K, T Higuchi, S Ohta, K Kohno, Y Kumon, S Sakaki. Neuroprotective nitric oxide synthase inhibitor reduces intracellular calcium accumulation following transient global ischemia in the gerbil. Neurosci Lett 224:17-20, 1997 Kojima I, T Tanaka, R Inagi, H Kato, T Yamashita, A Sakiyama, O Ohneda, N Takeda, M Sata, T Miyata, T Fujita, and M Nangaku. Protective role of hypoxia-inducible factor-2α against ischemic damage and oxidative stress in the kidney. J Am Soc Nephrol 18: 1218–1226, 2007. Kudo T, S Kanemoto, H Hara, N Morimoto, T Morihara, R Kimura, T Tabira, K Imaizumi, M Takeda. A molecular chaperone inducer protects neurons from ER stress. Cell Death Differ 15: 364-375, 2008. Kumagai T, M Nangaku, I Kojima, R Nagai, JR Ingelfinger, T Miyata, T Fujita, R Inagi. Glyoxalase I overexpression ameliorates renal ischemia-reperfusion injury in rats. Am J Physiol Renal Physiol 296: 912-921, 2009. Lee HT, CW Emala. Preconditioning and adenosine protect human proximal tubule cells in an in vitro model of ischemic injury. J Am Soc Nephrol 13: 2753–2761, 2002. Lingwal N, M Padmasekar, B Samikannu, RG Bretzel, KT Preissner, and T Linn. Inhibition of gelatinase B (matrix metalloprotease-9) activity reduces cellular inflammation and restores function of transplanted pancreatic islets. Diabetes 61: 2045–2053, 2012. Li Y, Y Guo, J Tang , J Jiang , Z Chen. New insights into the roles of CHOP-induced apoptosis in ER stress. Acta Biochim Biophys Sin (Shanghai) 46: 629-40, 2014. Liu S, B Hartleben, O Kretz, T Wiech, P Igarashi, N Mizushima, G Walz, TB Huber.Autophagy plays a critical role in kidney tubule maintenance, aging and ischemia-reperfusion injury. Autophagy 8: 826–837, 2012. Mahfoudh-Boussaid A, MA Zaouali, T Hauet, K Hadj-Ayed, AH Miled, S Ghoul- Mazgar, D Saidane-Mosbahi, J Rosello-Catafau, H Ben Abdennebi. Attenuation of endoplasmic reticulum stress and mitochondrial injury in kidney with ischemic postconditioning application and trimetazidine treatment. J Biomed Sci 19:71, 2012. Marwarha G, S Raza, JR Prasanthi, and O Ghribi. Gadd153 and NF-κB crosstalk regulates 27-hydroxycholesterol-induced increase in BACE1 and β-amyloid production in human neuroblastoma SH-SY5Y cells. PLoS One 8: e70773, 2013. Masuda M, S Miyazaki-Anzai, M Levi, TC Ting, and M Miyazaki. PERK-eIF2α-ATF4-CHOP signaling contributes to TNFα-induced vascular calcification. J Am Heart Assoc 2: e000238, 2013. Matsuyama M, R Yoshimura, Y Kawahito, H Sano, J Chargui, JL Touraine, and T Nakatani. Relationship between peroxisome proliferator-activated receptor-γ and renal ischemia-reperfusion injury. Mol Med Rep 1: 499–503, 2008. Mattiazzi M, M D'Aurelio, CD Gajewski, K Martushova, M Kiaei, MF Beal, and G Manfredi. Mutated human SOD1 causes dysfunction of oxidative phosphorylation in mitochondria of transgenic mice. J Biol Chem 277: 29626–29633, 2002. McCullough KD, JL Martindale, LO Klotz, TY Aw, and NJ Holbrook. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol 21: 1249–1259, 2001. Miyazaki Y, K Kaikita, M Endo, E Horio, M Miura, K Tsujita, S Hokimoto, M Yamamuro, T Iwawaki, T Gotoh, H Ogawa, and Y Oike. C/EBP homologous protein deficiency attenuates myocardial reperfusion injury by inhibiting myocardial apoptosis and inflammation. Arterioscler Thromb Vasc Biol 31: 1124–1132, 2011. Mizukami T, K Orihashi, B Herlambang, S Takahashi, M Hamaishi, K Okada, T Sueda. Sodium 4-phenylbutyrate protects against spinal cord ischemia by inhibition of endoplasmic reticulum stress. J Vasc Surg 52: 1580-1586., 2010 Moore F, I Santin, TC Nogueira, EN Gurzov, L Marselli, P Marchetti, and DL Eizirik. The transcription factor C/EBPδ has anti-apoptotic and anti-inflammatory roles in pancreatic beta cells. PLoS One 7: e31062, 2012. Murphy MP, A Holmgren, NG Larsson, B Halliwell, CJ Chang, B Kalyanaraman, SG Rhee, PJ Thornalley, L Partridge, D Gems, T Nystrom, V Belousov, PT Schumacker, and CC Winterbourn. Unraveling the biological roles of reactive oxygen species. Cell Metab 13: 361–366, 2011. Nishitoh H. CHOP is a multifunctional transcription factor in the ER stress response. J Biochem 151:217-9, 2012. Orsolic N, AH Knezevic, L Sver, S Terzic, I Basic. Immunomodulatory and antimetastatic action of propolis and related polyphenolic compounds. J Ethnopharmacol 94: 307–315, 2004. OyadomariS, M Mori. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11:381-9, 2004. Pan H, Q Jiang, J Yu, J Mei, Y Cui, W Zhao. Quercetin promotes cell apoptosis and inhibits the expression of MMP-9 and fibronectin via the AKT and ERK signalling pathways in human glioma cells. Neurochem Int 80C: 60-71, 2104. Park SH, HJ Choi, H Yang, KH Do, J Kim, DW Lee, and Y Moon. Endoplasmic reticulum stress-activated C/EBP homologous protein enhances nuclear factor-κB signals via repression of peroxisome proliferator-activated receptor gamma. J Biol Chem 285: 35330–35339, 2010. Peairs A, A Radjavi, S Davis, L Li, A Ahmed, S Giri, CM Reilly. Activation of AMPK inhibits inflammation in MRL/lpr mouse mesangial cells. Clin Exp Immunol 156: 542–551, 2009. Qi GM, LX Jia, YL Li, HH Li, J Du. Adiponectin suppresses angiotensin II-induced inflammation and cardiac fibrosis through activation of macrophage autophagy. Endocrinology 155: 2254–2265 2014. Ranganathan PV, C Jayakumar, R Mohamed, Z Dong, and G Ramesh. Netrin-1 regulates the inflammatory response of neutrophils and macrophages, and suppresses ischemic acute kidney injury by inhibiting COX-2-mediated PGE2 production. Kidney Int 83: 1087–1098, 2013. Roach PJ. AMPK → ULK1 → Autophagy. Mol Cell Biol 31: 3082–3084, 2011. Ron D, and JF Habener. CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription. Genes Dev 6:439-53, 1992. Schmitt-Ney M and JF Habener. CHOP/GADD153 gene expression response to cellular stresses inhibited by prior exposure to ultraviolet light wavelength band C (UVC). Inhibitory sequence mediating the UVC response localized to exon 1. J Biol Chem 275: 40839–40845, 2000. Singh D, V Chander, K Chopra. The effect of quercetin, a bioflavonoid on ischemia/reperfusion induced renal injury in rats. Arch Med Res 35: 484-494, 2004. Sun Y, LY Pu, L Lu, XH Wang, F Zhang, JH Rao. N-acetylcysteine attenuates reactive-oxygen-species-mediated endoplasmic reticulum stress during liver ischemia-reperfusion injury. World J Gastroenterol 20:15289-15298, 2014. Tajiri S, S Oyadomari, S Yano, M Morioka, T Gotoh, JI Hamada, Y Ushio, and M Mori. Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOP. Cell Death Differ 11: 403–415, 2004. Takagi H, Y Matsui, S Hirotani, H Sakoda, T Asano, J Sadoshima. AMPK mediates autophagy during myocardial ischemia in vivo. Autophagy 3: 405-407, 2007. Thatcher TH, HM Hsiao, E Pinner, M Laudon, SJ Pollock, PJ Sime, and RP Phipps. Neu-164 and Neu-107, two novel antioxidant and anti-myeloperoxidase compounds, inhibit acute cigarette smoke-induced lung inflammation. Am J Physiol Lung Cell Mol Physiol 305: L165–L174, 2013. Thurman JM. Triggers of inflammation after renal ischemia/reperfusion. Clin Immunol 123: 7–13, 2007. Turdi S, X Fan, J Li, J Zhao, AF Huff, M Du, J Ren. AMP-activated protein kinase deficiency exacerbates aging-induced myocardial contractile dysfunction. Aging Cell, 9: 592–606, 2010. Ubeda M, XZ Wang , H Zinszner, I Wu, JF Habener, D Ron. Stress-induced binding of the transcriptional factor CHOP to a novel DNA control element. Mol Cell Biol 16:1479-89, 1996. Viner RI, DA Ferrington, TD Williams, DJ Bigelow, C Schoneich. Protein modification during biological aging: selective tyrosine nitration of the SERCA2a isoform of the sarcoplasmic reticulum Ca2+-ATPase in skeletal muscle. Biochem J 340, 657–669, 1999. Wang LT, BL Chen, CT Wu, KH Huang, CK Chiang, SH Liu. Protective role of AMP-activated protein kinase-evoked autophagy on an in vitro model of ischemia/reperfusion-induced renal tubular cell injury. PLoS One 8: e79814, 2013. Wang XZ and D Ron. Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP kinase. Science 272: 1347–1349, 1996. Wheeler CR, JA Salzman, NM Elsayed, ST Omaye, and DW Korte Jr. Automated assays for superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activity. Anal Biochem 184: 193–199, 1990. Woolley JF, J Stanicka, and TG Cotter. Recent advances in reactive oxygen species measurement in biological systems. Trends Biochem Sci 38: 556–565, 2013. Wu CT, ML Sheu, KS Tsai, CK Chiang, and SH Liu. Salubrinal, an eIF2α dephosphorylation inhibitor, enhances cisplatin-induced oxidative stress and nephrotoxicity in a mouse model. Free Radic Biol Med 51: 671–680, 2011. Wu J, X Xu, Y Li, J Kou, F Huang, B Liu, K Liu. Quercetin, luteolin and epigallocatechin gallate alleviate TXNIP and NLRP3-mediated inflammation and apoptosis with regulation of AMPK in endothelial cells. Eur J Pharmacol 15: 745:59-68, 2014. Yoshida T, H Sugiura, M Mitobe, K Tsuchiya, S Shirota, S Nishimura, S Shiohira, H Ito, K Nobori, SR Gullans, T Akiba, and K Nitta. ATF3 protects against renal ischemia-reperfusion injury. J Am Soc Nephrol 19: 217–224, 2008. Yun Y, WG Duan, P Chen, HX Wu, ZQ Shen, ZY Qian, and DH Wang. Down-regulation of cyclooxygenase-2 is involved in ischemic postconditioning protection against renal ischemia reperfusion injury in rats. Transplant Proc 419: 3585–3589, 2009. Zahner G, G Wolf, S Schroeder, and RAK Stahl. Inhibition of platelet-derived growth factor-induced mesangial cell proliferation by cyclooxygenase-2 overexpression is abolished through reactive oxygen species. FEBS Lett 580: 2523–2528, 2006. Zinszner H, M Kuroda, X Wang, N Batchvarova, RT Lightfoot, H Remotti, JL Stevens, and D Ron. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 12: 982–995, 1998. Zou MH, Z Xie. Regulation of interplay between autophagy and apoptosis in the diabetic heart: new role of AMPK. Autophagy 9: 624–625, 2013. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/18298 | - |
dc.description.abstract | 腎臟缺血再灌流為最主要造成急性腎衰竭的原因之一,然而截至目前為止對其引起的損傷並無良好的治療方式且對其之機制仍未完全明瞭。目前已知氧化壓力為其重要的損傷機制之一,且最近的研究也發現腎臟缺血再灌流所引起之氧化壓力可以進一步引起內質網壓力最終造成腎臟的損傷及功能的喪失。CCAAT/enhancer結合蛋白同源蛋白(CCAAT/enhancer-binding protein homologous protein, CHOP)是一個重要的內質網壓力蛋白,其為一轉錄因子負責引發內質網壓力所造成之細胞凋亡。目前研究認為內質網壓力在腎臟缺血再灌流所引起之損傷中至為重要,但對於CHOP在其中所扮演的角色仍然不甚清楚,因此本研究希望同時利用動物及細胞模式來研究CHOP在腎臟缺血再灌流中所扮演的角色,並測試抗氧化物質槲皮素是否可以調控缺血再灌流所引起的CHOP表現及其他可能的保護機制。結果顯示,在處理缺血在灌流後,CHOP基因剔除小鼠之肌酐酸及尿素氮數值相較於野生基因型小鼠來的低,代表CHOP基因剔除小鼠其腎功能損傷較少。病理組織染色也觀察到類似的情形,CHOP基因剔除小鼠在腎臟缺血再灌流後其組織受損及免疫細胞浸潤的情況較輕微。進一步發現CHOP基因缺失可減低其缺血再灌流後的caspase-3, caspase-8的表現,也可減低脂質過氧化程度並增加內生性抗氧化物質的活性,顯示CHOP基因缺失的確可減低腎臟缺血再灌流所造成的氧化壓力。在缺血再灌流之細胞模式中,以微RNA抑制CHOP表現後可發現過氧化氫產生相較於對照組有顯著的下降,同時細胞凋亡及發炎反應分子表現也減少許多。內生性抗氧化物在CHOP抑制的情況下則有更強的活性。利用過氧化氫及內生性氧化壓力產生物menadione也可發現CHOP抑制減低了氧化壓力引起之細胞凋亡及發炎反應分子表現。抗氧化劑槲皮素過去已知可保護缺血再灌流造成的傷害。本研究發現,抑制槲皮素所誘發的細胞自噬反應會降低槲皮素的保護作用,由此可知除了抗氧化能力之外,槲皮素也能透過誘發細胞自噬作用減低缺血再灌流所造成的細胞傷害。近一步利用動物模式來觀察可以發現,槲皮素有效的降低腎臟缺血再灌流所造成的腎臟功能損失及組織的傷害。利用西方點墨法發現,槲皮素有效的降低了腎臟缺血再灌流所引起的CHOP表現。另外槲皮素也增加了adenosine monophosphate-activated protein kinase (AMPK)的磷酸化及誘發了細胞自噬作用,同時也降低mammalian target of rapamycin的磷酸化。進一步以螢光免疫染色發現,槲皮素的確增加細胞自噬小體的形成。由結果可知,在腎臟缺血再灌流的情況下,槲皮素的確顯著的加強了AMPK-自噬作用這條訊息傳遞路徑。總結來說,我們發現CHOP的表現不僅僅造成了細胞凋亡的產生,同時也會增加氧化壓力及發炎反應,抗氧化劑槲皮素有效的降低了缺血再灌流所造成的CHOP表現及活化了AMPK-自噬作用的路徑。在未來,調控內質網壓力的藥物及抗氧化劑槲皮素也許可成為治療腎臟缺血再灌流的可能策略。 | zh_TW |
dc.description.abstract | Renal ischemia-reperfusion (I/R) is a major cause of acute renal failure. Generation of reactive oxygen species was one of the most important mechanisms in renal I/R injury. Recent studies showed that ROS could induced renal cell death through ER stress activation. CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) is involved in the ER stress signaling pathways. CHOP is a transcription factor and a major mediator of ER stress-induced apoptosis. However, the role of CHOP in renal I/R injury is still undefined. Here, we investigated whether CHOP could regulate I/R-induced renal injury using CHOP-knockout mice and cultured renal tubular cells as models. In CHOP-knockout mice, loss of renal function induced by I/R was prevented. Renal proximal tubule damage was induced by I/R in wild-type mice; however, the degree of alteration was significantly less in CHOP-knockout mice. CHOP deficiency also decreased the I/R-induced activation of caspase-3 and -8, apoptosis, and lipid peroxidation, whereas the activity of endogenous antioxidants increased. In an in vitro I/R model, small interfering RNA targeting CHOP significantly reversed increases in H2O2 formation, inflammatory signals, and apoptotic signals, while enhancing the activity of endogenous antioxidants in renal tubular cells. To the best of our knowledge, this is the first study which demonstrates that CHOP deficiency attenuates oxidative stress and I/R-induced acute renal injury both in vitro and in vivo. Antioxidants such as quercetin are considered to be a potential therapeutic strategy for I/R in recent years. Quercetin could protect renal cell against injury induced by in vitro I/R model through adenosine monophosphate-activated protein kinase (AMPK)-autophagy pathway. In this studies, we found that quercetin attenuated I/R-induced renal damage in mice. Furthermore, quercetin treatment increased the phosphorylation of AMPK and the cleavage of microtubule-associated protein light chain 3 (LC3). We also found that quercetin could enhance the autophagasome formation by LC3 Immunofluorescence staining. Those results suggest AMPK-autophagy pathway may participated in the protective effects of quercetin in renal I/R. Taken together, our study indicate CHOP regulates not only apoptosis-related signaling but also ROS formation and inflammation in renal tubular cells during I/R. Antioxidant quercetin treatment could inhibit ER stress related signal expression and activate AMPK-autophagy pathway. In future, ER stress modulating compounds and quercetin may be potential therapeutic strategies for renal I/R. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T00:58:39Z (GMT). No. of bitstreams: 1 ntu-104-F96447008-1.pdf: 4368187 bytes, checksum: 455df76d4d0d3f1ae24b7bbd90c505a0 (MD5) Previous issue date: 2015 | en |
dc.description.tableofcontents | 目錄
口試委員會審定書 I 誌謝 IV Abstract VIII Abbreviation Summary X Part 1: Introduction 1 1.1 Renal ischemia and reperfusion 1 1.2 The role of ROS in renal I/R 2 1.3 ER stress activation in renal I/R 4 1.4 CHOP plays the important role in ER stress induced apoptosis 6 1.5 Emerging drug discovery opportunities for I/R through ER stress related signals pathway 8 1.6 Antioxidant quercetin 10 Part 2: Aims 12 Part 3: Materials and Methods 13 3.1 Experimental animals, I/R protocol, and sample preparation 13 3.2 Bone marrow transplantation 14 3.3 Histological examinations 15 3.4 Immunohistochemistry and immunofluorescence staining 16 3.5 TUNEL staining and caspase-3/7 activity assay 17 3.6 Cell culture 18 3.7 ATP depletion/repletion model (in vitro I/R model) 19 3.8 siRNA transfection 19 3.9 Immunoblotting analysis 20 3.10 Sub-G1 analysis for DNA fragmentation and Propidium iodide and annexin V double staining 21 3.11 Peroxy orange-1 staining, and dichlorodihydrofluorescein diacetate (DCFDA) staining 22 3.12 Measurement of endogenous antioxidants 22 3.13 Statistics 23 Part 4: Results 24 4.1 CHOP deficiency attenuated renal dysfunction after I/R 24 4.2 CHOP deficiency attenuated renal cell apoptosis and inflammatory cell infiltration after I/R 26 4.3 CHOP knockout inflammatory cells did not influence I/R-induced renal function lost 27 hypoxia/reoxygenation induced oxidative stress and renal tubular cell apoptosis and increases the activities of endogenous antioxidants 28 4.5 CHOP knockdown attenuated H2O2 and endogenous ROS generator-induced renal cell injury 29 4.6 Quercetin treatment enhanced AMPK-LC3 signaling pathway in ATP depletion/repletion (D/R) model in renal tubular cells 30 4.7 Quercetin pretreatment attenuated I/R-induced renal injury 31 4.8 Quercetin pretreatment enhanced AMPK-LC3 signaling pathway in mice renal I/R model 32 Part 5: Discussion 33 Part 6: Conclusion 43 Part 7: References 44 Part 8: Figures and figure legends 60 | |
dc.language.iso | en | |
dc.title | CHOP蛋白、氧化壓力及發炎反應在腎臟缺血再灌流引起細胞凋亡上之角色探討 | zh_TW |
dc.title | Roles of CCAAT/enhancer-binding Protein Homologous Protein (CHOP), Oxidative Stress and Inflammation in Renal Ischemia/Reperfusion-induced Cell Apoptosis | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 蕭水銀(Shoei-Yn Lin-Shiau),楊榮森(Rong-Sen Yang),唐德成(Der-Cherng Tarng),劉秉慧(Biing-Hui Liu),姜至剛(Chih-Kang Chiang) | |
dc.subject.keyword | 缺血再灌流,內質網壓力,CHOP蛋白,細胞凋亡,槲皮素,發炎反應, | zh_TW |
dc.subject.keyword | ischemia/reperfusion,ER stress,CHOP,quercetin,AMPK,autophagy, | en |
dc.relation.page | 98 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2015-01-28 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 毒理學研究所 | zh_TW |
顯示於系所單位: | 毒理學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-104-1.pdf 目前未授權公開取用 | 4.27 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。