内质网应激预处理对大鼠肝脏缺血再灌注损伤的保护作用
摘要
多种刺激包括缺氧、缺糖、病毒感染等都可以导致内质网应激。近年来很多证据表明内质网应激和许多疾病密切相关。内质网应激触发的未折叠蛋白反应通过关闭蛋白翻译、促进分子伴侣表达、促进错误折叠蛋白的转运与降解等机制降低内质网负荷,提示内质网应激预处理具有潜在的治疗作用。本实验通过建立了内质网应激预处理条件下的大鼠肝脏缺血再灌注损伤模型,探讨内质网应激预处理在体内的应用。
1.以衣霉素为内质网应激诱导剂,采用肝脏70%缺血再灌注损伤模型。动物分组:100μg/kg体重-4天、100μg/kg体重-5天、100μg/kg体重-6天、50μg/kg体重-5天、300μg/kg体重-5天、对照组,观察不同诱导时间与给药剂量情况下,术后血清转氨酶水平的变化。结果:给药100μg/kg体重诱导5天,大鼠术后转氨酶水平显著低于对照组。其它组与对照组无统计学差异。
2.将雄性Wistar大鼠分为4组:安慰剂-假手术组(A组)、预处理-假手术组(B组)、安慰剂-IR组(C组)、预处理-IR组(D组),检测各组动物术前及术后的血清转氨酶含量,肝脏形态学改变及肝组织GRP78的表达情况。结果:B组GRP78表达水平高于A组,提示衣霉素在体内成功诱导了内质网应激。D组术后转氨酶水平显著低于C组,病理切片观察D组肝脏组织损伤情况好于C组。在电镜下D组内质网结构较C组完整。
结论:本研究发现在特定的诱导时间与剂量条件下,衣霉素诱导的内质网应激预处理对大鼠肝脏缺血再灌注损伤有显著的保护作用,提示内质网应激预处理可能是肝脏外科新的治疗手段。
The accumulation of unfolded proteins in the endoplasmic reticulum (ER) represents a cellular stress induced by multiple stimuli and pathological conditions. These include hypoxia, oxidative injury, high-fat diet, hypoglycemia, protein inclusion bodies and viral infection. ER stress triggers an evolutionarily conserved series of signal transduction events, which constitutes the unfolded protein response. Resent reports showed that ER stress is associate with a lot of diseases. The initial intent of the UPR is to reestablish homeostasis and normal ER function, and adaptive mechanisms predominantly involve activation of transcriptional programs that induce expression of genes that are capable of enhancing the protein folding capacity of the ER and genes for ER-assisted degradation (ERAD). These adaptive mechanisms suggest the possibility of therapeutic approaches targeting ER stress in IR injury. In this study we established a rat IR injury model under preconditioning with ER stress and investigated the potential of therapeutic approaches targeting ER stress in IR injury in rats.
1. Establishing animal model with IR injury under ER stress preconditioning. SD rats were pretreated with the ER stress inducer tunicamycin (TM) before IR operation. For evaluating the protective effect of preconditioning with ER stress, animals were divided into a control group and five pretreated groups. Different dose of TM (50μg/kg body wt, 100μg/kg body wt, 300μg/kg body wt) and different inducing time (4d, 5d, 6d) were progressed in this study. Partial hepatic IR injury model (45 min of ischemia via vascular clamping and 24 h reperfusion) were established and the severity of liver damage was determined by measuring serum ALT and AST levels. At the dose of 100μg/kg body wt and 5d before operation, preconditioning ameliorated the IR injury significantly (serum ALT at 6h after reperfusion 1506.28±401.98 u/L versus 2671.33±565.53 u/L, serum AST at 6h after reperfusion 3139.71±989.31 versus 5949.83±1205.51 u/L, serum ALT at 12h after reperfusion 723.71±278.56u/L versus 1141.33±231.63u/L, serum AST 2562.00±1673.47 versus 2996.83±882.68u/L, p<0.05 respectively). But no protection occurred in other groups.
2. Verifying the protective effect of ER stress preconditioning. Male wistar rats were divided into control-sham group (A), TM-sham group (B), control-IR group (C) and TM-IR group (D). TM preconditioning in rats showed significantly protection against IR injury evidenced by lack alteration of serum ALT (109.14±22.26 versus 513.72±304.90 u/L p<0.05) and normal liver histology. Immunohistochemistry and Western blotting showed over expression of the ER stress–inducible chaperones glucose-regulated protein 78 (GRP78) in IR treated rats. High expression of GRP78 in TM-sham group compared with control-sham group implied that ER stress was induced by TM administration. More abundant ER was observed in preconditioning group compared with control group under transmission electron microscope (TEM) when IR injury occurred.
Conclusion: Preconditioning with ER stress ameliorates the severity of IR injury in certain condition. These findings suggest the possibility therapeutic approaches targeting ER stress in hepatic IR injury.
1.以衣霉素为内质网应激诱导剂,采用肝脏70%缺血再灌注损伤模型。动物分组:100μg/kg体重-4天、100μg/kg体重-5天、100μg/kg体重-6天、50μg/kg体重-5天、300μg/kg体重-5天、对照组,观察不同诱导时间与给药剂量情况下,术后血清转氨酶水平的变化。结果:给药100μg/kg体重诱导5天,大鼠术后转氨酶水平显著低于对照组。其它组与对照组无统计学差异。
2.将雄性Wistar大鼠分为4组:安慰剂-假手术组(A组)、预处理-假手术组(B组)、安慰剂-IR组(C组)、预处理-IR组(D组),检测各组动物术前及术后的血清转氨酶含量,肝脏形态学改变及肝组织GRP78的表达情况。结果:B组GRP78表达水平高于A组,提示衣霉素在体内成功诱导了内质网应激。D组术后转氨酶水平显著低于C组,病理切片观察D组肝脏组织损伤情况好于C组。在电镜下D组内质网结构较C组完整。
结论:本研究发现在特定的诱导时间与剂量条件下,衣霉素诱导的内质网应激预处理对大鼠肝脏缺血再灌注损伤有显著的保护作用,提示内质网应激预处理可能是肝脏外科新的治疗手段。
The accumulation of unfolded proteins in the endoplasmic reticulum (ER) represents a cellular stress induced by multiple stimuli and pathological conditions. These include hypoxia, oxidative injury, high-fat diet, hypoglycemia, protein inclusion bodies and viral infection. ER stress triggers an evolutionarily conserved series of signal transduction events, which constitutes the unfolded protein response. Resent reports showed that ER stress is associate with a lot of diseases. The initial intent of the UPR is to reestablish homeostasis and normal ER function, and adaptive mechanisms predominantly involve activation of transcriptional programs that induce expression of genes that are capable of enhancing the protein folding capacity of the ER and genes for ER-assisted degradation (ERAD). These adaptive mechanisms suggest the possibility of therapeutic approaches targeting ER stress in IR injury. In this study we established a rat IR injury model under preconditioning with ER stress and investigated the potential of therapeutic approaches targeting ER stress in IR injury in rats.
1. Establishing animal model with IR injury under ER stress preconditioning. SD rats were pretreated with the ER stress inducer tunicamycin (TM) before IR operation. For evaluating the protective effect of preconditioning with ER stress, animals were divided into a control group and five pretreated groups. Different dose of TM (50μg/kg body wt, 100μg/kg body wt, 300μg/kg body wt) and different inducing time (4d, 5d, 6d) were progressed in this study. Partial hepatic IR injury model (45 min of ischemia via vascular clamping and 24 h reperfusion) were established and the severity of liver damage was determined by measuring serum ALT and AST levels. At the dose of 100μg/kg body wt and 5d before operation, preconditioning ameliorated the IR injury significantly (serum ALT at 6h after reperfusion 1506.28±401.98 u/L versus 2671.33±565.53 u/L, serum AST at 6h after reperfusion 3139.71±989.31 versus 5949.83±1205.51 u/L, serum ALT at 12h after reperfusion 723.71±278.56u/L versus 1141.33±231.63u/L, serum AST 2562.00±1673.47 versus 2996.83±882.68u/L, p<0.05 respectively). But no protection occurred in other groups.
2. Verifying the protective effect of ER stress preconditioning. Male wistar rats were divided into control-sham group (A), TM-sham group (B), control-IR group (C) and TM-IR group (D). TM preconditioning in rats showed significantly protection against IR injury evidenced by lack alteration of serum ALT (109.14±22.26 versus 513.72±304.90 u/L p<0.05) and normal liver histology. Immunohistochemistry and Western blotting showed over expression of the ER stress–inducible chaperones glucose-regulated protein 78 (GRP78) in IR treated rats. High expression of GRP78 in TM-sham group compared with control-sham group implied that ER stress was induced by TM administration. More abundant ER was observed in preconditioning group compared with control group under transmission electron microscope (TEM) when IR injury occurred.
Conclusion: Preconditioning with ER stress ameliorates the severity of IR injury in certain condition. These findings suggest the possibility therapeutic approaches targeting ER stress in hepatic IR injury.
引文
1. Anelli, T. & Sitia, R. Protein quality control in the early secretory pathway. EMBo J. (2008)27, 315–327.
2. Pizzo, P. & Pozzan, T. Mitochondria-endoplasmic reticulum choreography: structure and signaling dynamics. Trends Cell Biol. (2007)17, 511–517.
3. Ma, Y. & Hendershot, L. M. ER chaperone functions during normal and stress conditions. J. Chem. Neuroanat. (2004)28, 51–65.
4. Ron, D. & Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nature Rev. Mol. Cell. Biol. (2007)8, 519–529.
5. Malhotra, J. D. & Kaufman, R. J. The endoplasmic reticulum and the unfolded protein response. Semin. Cell Dev. Biol. (2007)18, 716–731.
6. Frand, A. R., Cuozzo, J. W. & Kaiser, C. A. Pathways for protein disulphide bond formation. Trends Cell Biol. (2000)10, 203–210.
7. Ozcan, U. et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science (2004)306, 457–461.
8. Xu, C., Bailly-Maitre, B. & Reed, J. C. Endoplamic reticulum stress: cell life and death decisions. J. Clin. Invest. (2005)115, 2656–2664.
9. Wu, J. & Kaufman, R. J. From acute ER stress to physiological roles of the unfolded protein response. Cell Death Differ. (2006)13, 374–384.
10. Kaneko, M., Niinuma, Y. & Nomura, Y. Activation signal of nuclear factor-κB in response to endoplasmic reticulum stress is transduced via IRE1 and tumor necrosis factor receptor-associated factor 2. Biol. Pharm. Bull. (2003)26, 931–935.
11. Egger, L. et al. Serine proteases mediate apoptosis-like cell death and phagocytosis under caspase-inhibiting conditions. Cell Death Differ.(2003)10, 1188–1203.
12. Ogata, M. et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol. Cell. Biol. (2006)26, 9220–9231.
13. Bernales, S., McDonald, K. L. & Walter, P. Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol. (2006)4, e423.
14. Schroder, M. & Kaufman, R. J. ER stress and the unfolded protein response. Mutat. Res. (2005)569, 29–63.
15. Rao, R. V. & Bredesen, D. E. Misfolded proteins, endoplasmic reticulum stress and neurodegeneration. Curr. opin. Cell Biol. (2004)16, 653–662.
16. Hollien, J. & Weissman, J. S. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science (2006)313, 104–107.
17. Zhang, K. et al. The unfolded protein response sensor IRE1αis required at 2 distinct steps in B cell lymphopoiesis. J. Clin. Invest. (2005)115, 268–281.
18. Lee, K. et al. IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merges to regulate XBP1 in signaling the unfolded protein response. Genes Dev. (2002)16, 452–466.
19. Travers, K. J. et al. Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell (2000)101, 249–258.
20. Urano, F. et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science (2000)287, 664–666.
21. Nishitoh, H. et al. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev. (2002)16, 1345–1355.
22. Yamamoto, K., Ichijo, H. & Korsmeyer, S. J. BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G2/M. Mol. Cell. Biol. (1999)19, 8469–8478.
23. Danial, N. N. & Korsmeyer, S. J. Cell death: critical control points. Cell (2004)116, 205–219.
24. Hetz, C. et al. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1α. Science (2006)312, 572–576.
25. Lei, K. & Davis, R. J. JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc. Natl Acad. Sci. USA (2003)100, 2432–2437.
26. Putcha, G. V. et al. JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Neuron (2003)38, 899–914.
27. Yamamoto, K., Ichijo, H. & Korsmeyer, S. J. BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G2/M. Mol. Cell. Biol. (1999)19, 8469–8478.
28. Srivastava, R. K. et al. Bcl-2 and Bcl-XL block thapsigargin-induced nitric oxide generation, c-Jun NH2-terminal kinase activity, and apoptosis. Mol. Cell. Biol. (1999)19, 5659–5674.
29. Yoneda, T. et al. Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J. Biol. Chem. (2001)276, 13935–13940.
30. Szegezdi, E., Fitzgerald, U. & Samali, A. Caspase-12 and ER-stress-mediated apoptosis: the story so far. Ann. NY Acad. Sci. (2003)1010, 186–194.
31. Lu, P. D., Harding, H. P. & Ron, D. Translation reinitiation at alternativeopen reading frames regulates gene expression in an integrated stress response. J. Cell Biol. (2004)167, 27–33.
32. Harding, H. P. et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell 11, (2003)619–633.
33. Harding, H. P., Zhang, Y., Bertolotti, A., Zeng, H. & Ron, D. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol. Cell (2000)5, 897–904.
34. Scheuner, D. et al. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol. Cell (2001)7, 1165–1176.
35. Boyce, M. et al. A selective inhibitor of eIF2αdephosphorylation protects cells from ER stress. Science (2005)307, 935–939.
36. Kouroku, Y. et al. ER stress (PERK/eIF2αphosphorylation) mediates the polyglutamineinduced LC3 conversion, an essential step for autophagy formation. Cell Death Differ. (2007)14, 230–239.
37. Fujita, E. et al. Two endoplasmic reticulum-associated degradation (ERAD) systems for the novel variant of the mutant dysferlin: ubiquitin/proteasome ERAD (I) and autophagy/lysosome ERAD(II). Hum. Mol. Genet. (2007)16, 618–629.
38. Ye, J. et al. ER stress induces cleavage of membranebound ATF6 by the same proteases that process SREBPs. Mol. Cell (2000)6, 1355–1364.
39. Yamamoto, K. et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6αand XBP1. Dev. Cell (2007)13, 365–376.
40. Wu, J. et al. ATF6αoptimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev. Cell (2007)13, 351–364.
41. Thuerauf, D. J., Marcinko, M., Belmont, P. J. & Glembotski, C. C. Effectsof the isoform-specific characteristics of ATF6αand ATF6βon endoplasmic reticulum stress response gene expression and cell viability. J. Biol. Chem. (2007)282, 22865–22878.
42. Belmont, P. J. et al. Coordination of growth and endoplasmic reticulum stress signaling by regulator of calcineurin 1 (RCAN1), a novel ATF6-inducible gene. J. Biol. Chem. (2008)283, 14012–14021.
43. Wang, H. G. et al. Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science (1999)284, 339–343.
44. Ma, Y., Brewer, J. W., Diehl, J. A. & Hendershot, L. M. Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J. Mol. Biol. (2002)318, 1351–1365.
45. Oyadomari, S. & Mori, M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. (2004)11, 381–389.
46. Harding, H. P. et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell (2000)6, 1099–1108.
47. Wang, X. Z. & Ron, D. Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP kinase. Science (1996)272, 1347–1349.
48. McCullough, K. D., Martindale, J. L., Klotz, L. O., Aw, T. Y. & Holbrook, N. J. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol. Cell. Biol. (2001)21, 1249–1259.
49. Marciniak, S. J. et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. (2004)18, 3066–3077.
50. Song, B., Scheuner, D., Ron, D., Pennathur, S. & Kaufman, R. J. Chopdeletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes. J. Clin. Invest. (2008)118, 3378–3389.
51. Puthalakath, H. et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell (2007)129, 1337–1349.
52. McCullough, K. D., Martindale, J. L., Klotz, L. O., Aw, T. Y. & Holbrook, N. J. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol. Cell. Biol. (2001)21, 1249–1259.
53. Ubeda, M. et al. Stress-induced binding of the transcriptional factor CHOP to a novel DNA control element. Mol. Cell. Biol. (1996)16, 1479–1489.
54. Nakagawa T, Yuan J. Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J Cell Biol (2000)150:887–894.
55. Nakagawa T, Zhu H, Morishima N et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature (2000)403:98–103.
56. Tan Y, Dourdin N, Wu C, De Veyra T, Elce JS, Greer PA.) Ubiquitous calpains promote caspase-12 and JNK activation during endoplasmic reticulum stress-induced apoptosis. J Biol Chem (2006)281:16016–16024.
57. Morishima N, Nakanishi K, Takenouchi H, Shibata T, Yasuhiko Y. An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome c-independent activation of caspase-9 by caspase-12. J Biol Chem (2002)277:34287–34294.
58. Rao RV, Castro-Obregon S, Frankowski H et al. Coupling endoplasmic reticulum stress to the cell death program. An Apaf-1-independent intrinsicpathway. J Biol Chem (2002)277:21836–21842.
59. Fischer H, Koenig U, Eckhart L, Tschachler E. Human caspase 12 has acquired deleterious mutations. Biochem Biophys Res Commun (2002)293:722–726.
60. Hitomi J, Katayama T, Eguchi Y et al. Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. J Cell Biol (2004)165:347–356.
61. Harding HP, Novoa I, Zhang Y et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell (2000)6:1099–1108.
62. Fawcett TW, Martindale JL, Guyton KZ, Hai T, Holbrook NJ. Complexes containing activating transcription factor (ATF)/cAMP–responsive -element-binding protein (CREB) interact with the CCAAT/enhancer -binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response. Biochem J (1999)339(Pt 1):135–141.
63. Lin JH, Li H, Zhang Y, Ron D, Walter P. Divergent effects of PERK and IRE1 signaling on cell viability. PLoS ONE (2009) 4:e4170.
64. Zinszner H, Kuroda M, Wang X et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev (1998)12:982–995.
65. McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol (2001)21:1249–1259.
66. Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol (2003)23:7198–7209.
67. Venugopal R, Jaiswal AK. Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes. Oncogene (1998)17:3145–3156.
68. He CH, Gong P, Hu B et al. Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation. J Biol Chem (2001)276:20858–20865.
69. Nguyen T, Sherratt PJ, Nioi P, Yang CS, Pickett CB. Nrf2 controls constitutive and inducible expression of ARE-driven genes through a dynamic pathway involving nucleocytoplasmic shuttling by Keap1. J Biol Chem (2005)280:32485–32492.
70. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D. Coupling of stress in the ER to activation of JNK protein kinase by transmembrane protein kinase IRE1. Science (2000)287:664–666.
71. Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K. Takeda. ASK1 is essential for endoplasmic reticulum stressinduced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev (2002) 16:1345–1355.
72. Lin JH, Li H, Yasumura D et al . IRE1 signaling affects cell fate during the unfolded protein response. Science (2007)318:944– 949.
73. Mendes CS, Levet C, Chatelain G, et al. ER stress protects from retinal degeneration. EMBO J. (2009) May 6; 28(9):1296-307.
74. Pizzo P, Pozzan T. Mitochondria-endoplasmic reticulum choreography: structure and signaling dynamics. Trends Cell Biol (2007)17:511–517.
75. Zong WX, Li C, Hatzivassiliou G et al. Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis. J Cell Biol (2003)162:59–69.
76. Shirasugi N, Wakabayashi G, ShimazuM, et al. Up - regulation of oxygen derived free radicals by interleukin - l in hepatic ischemia / reperfusion injury[ J ]. Transp lantation, (1997) 64 (6): 1398 -1403.
77. Clarien PA, Harvey PR, Strasberg SM. Preservation and reperfusion injuries in liver allografts. Transp lantation, (l992) 53 (5): 957- 958.
78. Tanaka, S., Uehara, T. & Nomura, Y. Up-regulation of protein-disulfide isomerase in response to hypoxia/brain ischemia and its protective effect against apoptotic cell death. J. Biol. Chem. (2000)275, 10388–10393.
79. Xu, L., Eu, J. P., Meissner, G. & Stamler, J. S. Activation of the cardiac calcium release channel (ryanodine receptor) by poly-S-nitrosylation. Science (1998)279, 234–237.
80. Viner, R. I., Ferrington, D. A., Williams, T. D., Bigelow, D. J. & Schoneich, C. Protein modification during biological aging: selective tyrosine nitration of the SERCA2a isoform of the sarcoplasmic reticulum Ca2+- ATPase in skeletal muscle. Biochem. J. (1999)340, 657–669.
81. Xu, K. Y., Huso, D. L., Dawson, T. M., Bredt, D. S. & Becker, L. C. Nitric oxide synthase in cardiac sarcoplasmic reticulum. Proc. Natl Acad. Sci. USA (1999)96, 657–662.
82. Kumar, R. et al. Brain ischemia and reperfusion activates the eukaryotic initiation factor 2αkinase, PERK. J. Neurochem. (2001)77, 1418–1421.
83. Paschen, W., Gissel, C., Linden, T., Althausen, S. & Doutheil, J. Activation of gadd153 expression through transient cerebral ischemia: evidence that ischemia causes endoplasmic reticulum dysfunction. Brain Res. Mol. Brain Res. (1998)60, 115–122.
84. Tajiri, S. et al. Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOP. Cell Death Differ.(2004)11, 403–415.
85. Kohno, K., Higuchi, T., Ohta, S., Kumon, Y. & Sakaki, S. Neuroprotective nitric oxide synthase inhibitor reduces intracellular calcium accumulation following transient global ischemia in the gerbil. Neurosci. Lett. (1997)224, 17–20.
86. Iadecola, C., Zhang, F., Casey, R., Nagayama, M. & Ross, M. E. Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J. Neurosci. (1997)17, 9157–9164.
87. Hynes, J. Jr & Leftheri, K. Small molecule p38 inhibitors: novel structural features and advances from 2002–2005 Curr. Top. Med. Chem. (2005)5, 967–985.
88. Lee, M. R. & Dominguez, C. MAP kinase p38 inhibitors: clinical results and an intimate look at their interactions with p38αprotein. Curr. Med. Chem. (2005)12, 2979–2994.
89. Puthalakath, H. et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell (2007)129, 1337–1349.
90. Kudo, T., Imaizumi, K. & Hara, H. A molecular chaperone inducer as potential therapeutic agent for neurodegenerative disease. Nihon Shinkei Seishin Yakurigaku Zasshi (2007)27, 63–67.
91. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Cirulatiom; (1986)74:1124.
92. Koti RS, Seifaliam AM, Davidson BR. Protection of the liver by ischemic preconditioning: a review of mechanisms and clinical applications. Dig Surg. (2003)20(5):283-96.
93. Ambros JT, Herrero-Fresneda I, Borau OG, Boira JM. Ischemicpreconditioning in solid organ transplantation: from experimental to clinics. Transpl Int. (2007)20(3):219-29.
94. Shintani-Ishida K, Nakajima M, Uemura K, Yoshida K. Ischemic preconditioning protects cardiomycytes against ischemic injury by inducing GRP78. Biochem Biophys Res Commun. (2006)14; 345(4):1600-5.
95. Pan YX, Ren AJ, Zheng J, Rong WF, Chen H, Yan XH, Wu C, Yuan WJ, Lin L. Delayed cytoprotection induced by hypoxic preconditioning in cultured neonatal rat cardiomyocytes: role of GRP78. Life Sci. Sep (2007)8; 81(13):1042-9.
96. Rao RV, Peel A, Logvinova A, del Rio G, Hermel E, Yoota T, Goldsmith PC, Ellerby LM, Ellerby HM, Bredesen DE. Coupling endoplasmic reticulum stress to the cell death program: role of the ER chaperone GRP78. FEBS Lett. (2002)13; 514(2-3):122-8.
97. Hayashi T, Saito A, Okuno S, Ferrand-Drake M, Chan PH. Induction of Grp78 by ischemic preconditioning reduces endoplasmic reticulum stress and prevents delayed neuronal cell death. J Cereb Blood Flow Metab. (2003)23(8):949-61.
98. Dawson, R.M.C., et al., Data for Biochemical Research, 3rd ed., p. 335., Oxford University Press, New York, (1986)
99. Hideaki Tamaki and Shohei Yamashina. In vivo effects of tunicamycin on the secretory processes of rat parotid glands. Cell Tissue Res (1987)250:323-330.
100.Satoshi Yokose and Yoshifumi Tajima. In vivo effects of tunicamycin on chondrocytes of rat mandibular condyles as revealed by lectin cytochemistry. Cell Tissue Res (1992)269:235-239.
101.Reiko Inagi, Takanori Kumagai, Hiroshi Nishi, Takahisa Kawakami, ToshioMiyata,Toshiro Fujita,and Masaomi Nangaku. Preconditioning with Endoplasmic Reticulum Stress Ameliorates Mesangioproliferative Glomerulonephritis. J Am Soc Nephrol, (2008)19: 915–922.
102.Yin DP, Sankary H, Chong A, et al. Protective effect of ischemic preconditioning on liver p reservation - reperfusion injury in rats. Transplantation. (1998)66 (2): 152 - 157.
103.Morris JA, Dorner AJ, Edwards CA, Hendershot LM, Kaufman RJ: Immunoglobulin binding protein (BiP) function is required to protect cells from endoplasmic reticulum stress but is not required for the secretion of selective proteins. J Biol Chem (1997)272: 4327–4334.
104.Vilatoba M, Eckstein C, Bilbao G, et al. Sodium 4-phenylbutyrate protects against liver ischemia reperfusion injury by inhibition of endoplasmic reticulum-stress mediated apoptosis. Surgery; (2005)138: 342.
105.Qi X, Hosoi T, Okuma Y, et al. Sodium 4-phenylbutyrate protects against cerebral ischemic injury. Mol Pharmacol; (2004)66: 899.
106.Izuhara Y, Nangaku M, Takizawa S, et al. A novel class of advanced glycation inhibitors ameliorates renal and cardiovascular damage in experimental rat models. Nephrol Dial Transplant; (2008)23: 497.
107.Ma FY, Flanc RS, Tesch GH, et al. A pathogenic role for c-Jun aminoterminal kinase signaling in renal fibrosis and tubular cell apoptosis. J Am Soc Nephrol; (2007)18: 472.
108.Pallet N, Bouvier N, Bendjallabah A, et al. Cyclosporine-induced endoplasmic reticulum stress triggers tubular phenotypic changes and death. Am J Transplant; (2008)8: 2283.
109.Zhang PL, Lun M, Teng J, et al. Preinduced molecular chaperones in the endoplasmic reticulum protect cardiomyocytes from lethal injury. Ann ClinLab Sci; (2004)34: 449.
110.Hung CC, Ichimura T, Stevens JL, et al. Protection of renal epithelial cells against oxidative injury by endoplasmic reticulum stress pre-conditioning is mediated by ERK1/2 activation. J Biol Chem; (2003)278: 29317.
2. Pizzo, P. & Pozzan, T. Mitochondria-endoplasmic reticulum choreography: structure and signaling dynamics. Trends Cell Biol. (2007)17, 511–517.
3. Ma, Y. & Hendershot, L. M. ER chaperone functions during normal and stress conditions. J. Chem. Neuroanat. (2004)28, 51–65.
4. Ron, D. & Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nature Rev. Mol. Cell. Biol. (2007)8, 519–529.
5. Malhotra, J. D. & Kaufman, R. J. The endoplasmic reticulum and the unfolded protein response. Semin. Cell Dev. Biol. (2007)18, 716–731.
6. Frand, A. R., Cuozzo, J. W. & Kaiser, C. A. Pathways for protein disulphide bond formation. Trends Cell Biol. (2000)10, 203–210.
7. Ozcan, U. et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science (2004)306, 457–461.
8. Xu, C., Bailly-Maitre, B. & Reed, J. C. Endoplamic reticulum stress: cell life and death decisions. J. Clin. Invest. (2005)115, 2656–2664.
9. Wu, J. & Kaufman, R. J. From acute ER stress to physiological roles of the unfolded protein response. Cell Death Differ. (2006)13, 374–384.
10. Kaneko, M., Niinuma, Y. & Nomura, Y. Activation signal of nuclear factor-κB in response to endoplasmic reticulum stress is transduced via IRE1 and tumor necrosis factor receptor-associated factor 2. Biol. Pharm. Bull. (2003)26, 931–935.
11. Egger, L. et al. Serine proteases mediate apoptosis-like cell death and phagocytosis under caspase-inhibiting conditions. Cell Death Differ.(2003)10, 1188–1203.
12. Ogata, M. et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol. Cell. Biol. (2006)26, 9220–9231.
13. Bernales, S., McDonald, K. L. & Walter, P. Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol. (2006)4, e423.
14. Schroder, M. & Kaufman, R. J. ER stress and the unfolded protein response. Mutat. Res. (2005)569, 29–63.
15. Rao, R. V. & Bredesen, D. E. Misfolded proteins, endoplasmic reticulum stress and neurodegeneration. Curr. opin. Cell Biol. (2004)16, 653–662.
16. Hollien, J. & Weissman, J. S. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science (2006)313, 104–107.
17. Zhang, K. et al. The unfolded protein response sensor IRE1αis required at 2 distinct steps in B cell lymphopoiesis. J. Clin. Invest. (2005)115, 268–281.
18. Lee, K. et al. IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merges to regulate XBP1 in signaling the unfolded protein response. Genes Dev. (2002)16, 452–466.
19. Travers, K. J. et al. Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell (2000)101, 249–258.
20. Urano, F. et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science (2000)287, 664–666.
21. Nishitoh, H. et al. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev. (2002)16, 1345–1355.
22. Yamamoto, K., Ichijo, H. & Korsmeyer, S. J. BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G2/M. Mol. Cell. Biol. (1999)19, 8469–8478.
23. Danial, N. N. & Korsmeyer, S. J. Cell death: critical control points. Cell (2004)116, 205–219.
24. Hetz, C. et al. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1α. Science (2006)312, 572–576.
25. Lei, K. & Davis, R. J. JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc. Natl Acad. Sci. USA (2003)100, 2432–2437.
26. Putcha, G. V. et al. JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Neuron (2003)38, 899–914.
27. Yamamoto, K., Ichijo, H. & Korsmeyer, S. J. BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G2/M. Mol. Cell. Biol. (1999)19, 8469–8478.
28. Srivastava, R. K. et al. Bcl-2 and Bcl-XL block thapsigargin-induced nitric oxide generation, c-Jun NH2-terminal kinase activity, and apoptosis. Mol. Cell. Biol. (1999)19, 5659–5674.
29. Yoneda, T. et al. Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J. Biol. Chem. (2001)276, 13935–13940.
30. Szegezdi, E., Fitzgerald, U. & Samali, A. Caspase-12 and ER-stress-mediated apoptosis: the story so far. Ann. NY Acad. Sci. (2003)1010, 186–194.
31. Lu, P. D., Harding, H. P. & Ron, D. Translation reinitiation at alternativeopen reading frames regulates gene expression in an integrated stress response. J. Cell Biol. (2004)167, 27–33.
32. Harding, H. P. et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell 11, (2003)619–633.
33. Harding, H. P., Zhang, Y., Bertolotti, A., Zeng, H. & Ron, D. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol. Cell (2000)5, 897–904.
34. Scheuner, D. et al. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol. Cell (2001)7, 1165–1176.
35. Boyce, M. et al. A selective inhibitor of eIF2αdephosphorylation protects cells from ER stress. Science (2005)307, 935–939.
36. Kouroku, Y. et al. ER stress (PERK/eIF2αphosphorylation) mediates the polyglutamineinduced LC3 conversion, an essential step for autophagy formation. Cell Death Differ. (2007)14, 230–239.
37. Fujita, E. et al. Two endoplasmic reticulum-associated degradation (ERAD) systems for the novel variant of the mutant dysferlin: ubiquitin/proteasome ERAD (I) and autophagy/lysosome ERAD(II). Hum. Mol. Genet. (2007)16, 618–629.
38. Ye, J. et al. ER stress induces cleavage of membranebound ATF6 by the same proteases that process SREBPs. Mol. Cell (2000)6, 1355–1364.
39. Yamamoto, K. et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6αand XBP1. Dev. Cell (2007)13, 365–376.
40. Wu, J. et al. ATF6αoptimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev. Cell (2007)13, 351–364.
41. Thuerauf, D. J., Marcinko, M., Belmont, P. J. & Glembotski, C. C. Effectsof the isoform-specific characteristics of ATF6αand ATF6βon endoplasmic reticulum stress response gene expression and cell viability. J. Biol. Chem. (2007)282, 22865–22878.
42. Belmont, P. J. et al. Coordination of growth and endoplasmic reticulum stress signaling by regulator of calcineurin 1 (RCAN1), a novel ATF6-inducible gene. J. Biol. Chem. (2008)283, 14012–14021.
43. Wang, H. G. et al. Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science (1999)284, 339–343.
44. Ma, Y., Brewer, J. W., Diehl, J. A. & Hendershot, L. M. Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J. Mol. Biol. (2002)318, 1351–1365.
45. Oyadomari, S. & Mori, M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. (2004)11, 381–389.
46. Harding, H. P. et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell (2000)6, 1099–1108.
47. Wang, X. Z. & Ron, D. Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP kinase. Science (1996)272, 1347–1349.
48. McCullough, K. D., Martindale, J. L., Klotz, L. O., Aw, T. Y. & Holbrook, N. J. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol. Cell. Biol. (2001)21, 1249–1259.
49. Marciniak, S. J. et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. (2004)18, 3066–3077.
50. Song, B., Scheuner, D., Ron, D., Pennathur, S. & Kaufman, R. J. Chopdeletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes. J. Clin. Invest. (2008)118, 3378–3389.
51. Puthalakath, H. et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell (2007)129, 1337–1349.
52. McCullough, K. D., Martindale, J. L., Klotz, L. O., Aw, T. Y. & Holbrook, N. J. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol. Cell. Biol. (2001)21, 1249–1259.
53. Ubeda, M. et al. Stress-induced binding of the transcriptional factor CHOP to a novel DNA control element. Mol. Cell. Biol. (1996)16, 1479–1489.
54. Nakagawa T, Yuan J. Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J Cell Biol (2000)150:887–894.
55. Nakagawa T, Zhu H, Morishima N et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature (2000)403:98–103.
56. Tan Y, Dourdin N, Wu C, De Veyra T, Elce JS, Greer PA.) Ubiquitous calpains promote caspase-12 and JNK activation during endoplasmic reticulum stress-induced apoptosis. J Biol Chem (2006)281:16016–16024.
57. Morishima N, Nakanishi K, Takenouchi H, Shibata T, Yasuhiko Y. An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome c-independent activation of caspase-9 by caspase-12. J Biol Chem (2002)277:34287–34294.
58. Rao RV, Castro-Obregon S, Frankowski H et al. Coupling endoplasmic reticulum stress to the cell death program. An Apaf-1-independent intrinsicpathway. J Biol Chem (2002)277:21836–21842.
59. Fischer H, Koenig U, Eckhart L, Tschachler E. Human caspase 12 has acquired deleterious mutations. Biochem Biophys Res Commun (2002)293:722–726.
60. Hitomi J, Katayama T, Eguchi Y et al. Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. J Cell Biol (2004)165:347–356.
61. Harding HP, Novoa I, Zhang Y et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell (2000)6:1099–1108.
62. Fawcett TW, Martindale JL, Guyton KZ, Hai T, Holbrook NJ. Complexes containing activating transcription factor (ATF)/cAMP–responsive -element-binding protein (CREB) interact with the CCAAT/enhancer -binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response. Biochem J (1999)339(Pt 1):135–141.
63. Lin JH, Li H, Zhang Y, Ron D, Walter P. Divergent effects of PERK and IRE1 signaling on cell viability. PLoS ONE (2009) 4:e4170.
64. Zinszner H, Kuroda M, Wang X et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev (1998)12:982–995.
65. McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol (2001)21:1249–1259.
66. Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol (2003)23:7198–7209.
67. Venugopal R, Jaiswal AK. Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes. Oncogene (1998)17:3145–3156.
68. He CH, Gong P, Hu B et al. Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation. J Biol Chem (2001)276:20858–20865.
69. Nguyen T, Sherratt PJ, Nioi P, Yang CS, Pickett CB. Nrf2 controls constitutive and inducible expression of ARE-driven genes through a dynamic pathway involving nucleocytoplasmic shuttling by Keap1. J Biol Chem (2005)280:32485–32492.
70. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D. Coupling of stress in the ER to activation of JNK protein kinase by transmembrane protein kinase IRE1. Science (2000)287:664–666.
71. Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K. Takeda. ASK1 is essential for endoplasmic reticulum stressinduced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev (2002) 16:1345–1355.
72. Lin JH, Li H, Yasumura D et al . IRE1 signaling affects cell fate during the unfolded protein response. Science (2007)318:944– 949.
73. Mendes CS, Levet C, Chatelain G, et al. ER stress protects from retinal degeneration. EMBO J. (2009) May 6; 28(9):1296-307.
74. Pizzo P, Pozzan T. Mitochondria-endoplasmic reticulum choreography: structure and signaling dynamics. Trends Cell Biol (2007)17:511–517.
75. Zong WX, Li C, Hatzivassiliou G et al. Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis. J Cell Biol (2003)162:59–69.
76. Shirasugi N, Wakabayashi G, ShimazuM, et al. Up - regulation of oxygen derived free radicals by interleukin - l in hepatic ischemia / reperfusion injury[ J ]. Transp lantation, (1997) 64 (6): 1398 -1403.
77. Clarien PA, Harvey PR, Strasberg SM. Preservation and reperfusion injuries in liver allografts. Transp lantation, (l992) 53 (5): 957- 958.
78. Tanaka, S., Uehara, T. & Nomura, Y. Up-regulation of protein-disulfide isomerase in response to hypoxia/brain ischemia and its protective effect against apoptotic cell death. J. Biol. Chem. (2000)275, 10388–10393.
79. Xu, L., Eu, J. P., Meissner, G. & Stamler, J. S. Activation of the cardiac calcium release channel (ryanodine receptor) by poly-S-nitrosylation. Science (1998)279, 234–237.
80. Viner, R. I., Ferrington, D. A., Williams, T. D., Bigelow, D. J. & Schoneich, C. Protein modification during biological aging: selective tyrosine nitration of the SERCA2a isoform of the sarcoplasmic reticulum Ca2+- ATPase in skeletal muscle. Biochem. J. (1999)340, 657–669.
81. Xu, K. Y., Huso, D. L., Dawson, T. M., Bredt, D. S. & Becker, L. C. Nitric oxide synthase in cardiac sarcoplasmic reticulum. Proc. Natl Acad. Sci. USA (1999)96, 657–662.
82. Kumar, R. et al. Brain ischemia and reperfusion activates the eukaryotic initiation factor 2αkinase, PERK. J. Neurochem. (2001)77, 1418–1421.
83. Paschen, W., Gissel, C., Linden, T., Althausen, S. & Doutheil, J. Activation of gadd153 expression through transient cerebral ischemia: evidence that ischemia causes endoplasmic reticulum dysfunction. Brain Res. Mol. Brain Res. (1998)60, 115–122.
84. Tajiri, S. et al. Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOP. Cell Death Differ.(2004)11, 403–415.
85. Kohno, K., Higuchi, T., Ohta, S., Kumon, Y. & Sakaki, S. Neuroprotective nitric oxide synthase inhibitor reduces intracellular calcium accumulation following transient global ischemia in the gerbil. Neurosci. Lett. (1997)224, 17–20.
86. Iadecola, C., Zhang, F., Casey, R., Nagayama, M. & Ross, M. E. Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J. Neurosci. (1997)17, 9157–9164.
87. Hynes, J. Jr & Leftheri, K. Small molecule p38 inhibitors: novel structural features and advances from 2002–2005 Curr. Top. Med. Chem. (2005)5, 967–985.
88. Lee, M. R. & Dominguez, C. MAP kinase p38 inhibitors: clinical results and an intimate look at their interactions with p38αprotein. Curr. Med. Chem. (2005)12, 2979–2994.
89. Puthalakath, H. et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell (2007)129, 1337–1349.
90. Kudo, T., Imaizumi, K. & Hara, H. A molecular chaperone inducer as potential therapeutic agent for neurodegenerative disease. Nihon Shinkei Seishin Yakurigaku Zasshi (2007)27, 63–67.
91. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Cirulatiom; (1986)74:1124.
92. Koti RS, Seifaliam AM, Davidson BR. Protection of the liver by ischemic preconditioning: a review of mechanisms and clinical applications. Dig Surg. (2003)20(5):283-96.
93. Ambros JT, Herrero-Fresneda I, Borau OG, Boira JM. Ischemicpreconditioning in solid organ transplantation: from experimental to clinics. Transpl Int. (2007)20(3):219-29.
94. Shintani-Ishida K, Nakajima M, Uemura K, Yoshida K. Ischemic preconditioning protects cardiomycytes against ischemic injury by inducing GRP78. Biochem Biophys Res Commun. (2006)14; 345(4):1600-5.
95. Pan YX, Ren AJ, Zheng J, Rong WF, Chen H, Yan XH, Wu C, Yuan WJ, Lin L. Delayed cytoprotection induced by hypoxic preconditioning in cultured neonatal rat cardiomyocytes: role of GRP78. Life Sci. Sep (2007)8; 81(13):1042-9.
96. Rao RV, Peel A, Logvinova A, del Rio G, Hermel E, Yoota T, Goldsmith PC, Ellerby LM, Ellerby HM, Bredesen DE. Coupling endoplasmic reticulum stress to the cell death program: role of the ER chaperone GRP78. FEBS Lett. (2002)13; 514(2-3):122-8.
97. Hayashi T, Saito A, Okuno S, Ferrand-Drake M, Chan PH. Induction of Grp78 by ischemic preconditioning reduces endoplasmic reticulum stress and prevents delayed neuronal cell death. J Cereb Blood Flow Metab. (2003)23(8):949-61.
98. Dawson, R.M.C., et al., Data for Biochemical Research, 3rd ed., p. 335., Oxford University Press, New York, (1986)
99. Hideaki Tamaki and Shohei Yamashina. In vivo effects of tunicamycin on the secretory processes of rat parotid glands. Cell Tissue Res (1987)250:323-330.
100.Satoshi Yokose and Yoshifumi Tajima. In vivo effects of tunicamycin on chondrocytes of rat mandibular condyles as revealed by lectin cytochemistry. Cell Tissue Res (1992)269:235-239.
101.Reiko Inagi, Takanori Kumagai, Hiroshi Nishi, Takahisa Kawakami, ToshioMiyata,Toshiro Fujita,and Masaomi Nangaku. Preconditioning with Endoplasmic Reticulum Stress Ameliorates Mesangioproliferative Glomerulonephritis. J Am Soc Nephrol, (2008)19: 915–922.
102.Yin DP, Sankary H, Chong A, et al. Protective effect of ischemic preconditioning on liver p reservation - reperfusion injury in rats. Transplantation. (1998)66 (2): 152 - 157.
103.Morris JA, Dorner AJ, Edwards CA, Hendershot LM, Kaufman RJ: Immunoglobulin binding protein (BiP) function is required to protect cells from endoplasmic reticulum stress but is not required for the secretion of selective proteins. J Biol Chem (1997)272: 4327–4334.
104.Vilatoba M, Eckstein C, Bilbao G, et al. Sodium 4-phenylbutyrate protects against liver ischemia reperfusion injury by inhibition of endoplasmic reticulum-stress mediated apoptosis. Surgery; (2005)138: 342.
105.Qi X, Hosoi T, Okuma Y, et al. Sodium 4-phenylbutyrate protects against cerebral ischemic injury. Mol Pharmacol; (2004)66: 899.
106.Izuhara Y, Nangaku M, Takizawa S, et al. A novel class of advanced glycation inhibitors ameliorates renal and cardiovascular damage in experimental rat models. Nephrol Dial Transplant; (2008)23: 497.
107.Ma FY, Flanc RS, Tesch GH, et al. A pathogenic role for c-Jun aminoterminal kinase signaling in renal fibrosis and tubular cell apoptosis. J Am Soc Nephrol; (2007)18: 472.
108.Pallet N, Bouvier N, Bendjallabah A, et al. Cyclosporine-induced endoplasmic reticulum stress triggers tubular phenotypic changes and death. Am J Transplant; (2008)8: 2283.
109.Zhang PL, Lun M, Teng J, et al. Preinduced molecular chaperones in the endoplasmic reticulum protect cardiomyocytes from lethal injury. Ann ClinLab Sci; (2004)34: 449.
110.Hung CC, Ichimura T, Stevens JL, et al. Protection of renal epithelial cells against oxidative injury by endoplasmic reticulum stress pre-conditioning is mediated by ERK1/2 activation. J Biol Chem; (2003)278: 29317.