钙调神经磷酸酶/NFATc信号通路介导他克莫司诱导移植后糖尿病的研究进展

摘要/Abstract

摘要： 他克莫司(Tacrolimus, FK506)是目前国内外器官移植术后的首选抗排斥反应药物,它通过抑制钙调神经磷酸酶而发挥免疫抑制作用。移植术后糖尿病(Post-transplantation diabetes mellitus, PTDM)是器官移植后的一种常见的并发症,发病率为2%~53%。PTDM与FK506抑制钙调神经磷酸酶关系密切。FK506使钙调神经磷酸酶活性受到抑制,阻碍细胞浆中的T细胞活化核因子(NFATc)去磷酸化,使NFATc不能核转位,抑制其与靶DNA结合,导致启动子不能启动相关基因的转录,一方面影响β细胞的增殖、细胞凋亡以及胰岛素的分泌,使胰岛素水平降低,另一方面使胰岛素的靶组织对胰岛素的敏感性和反应性降低,从而导致PTDM的发生。

关键词: 他克莫司, 糖尿病, 钙调神经磷酸酶/NFATc信号通路

Abstract: Tacrolimus (FK506), a calcineurin phosphatase inhibitor, is the base anti-rejection drug after organ transplantation. Post-transplant diabetes mellitus (PTDM) is a complication after a solid organ transplant, and its incidence is widely variable, ranging from 2% to 53%. Tacrolimus is an important risk of PTDM. Tacrolimus inhibits the dephosphorylation of the nuclear factor of activated T-cells (NFATc) in cytoplasm by inhibiting the function of the calcineurin. Then the transport of NFATc into the nucleus and combination with the target DNA are impaired. As a consequence, the promoter cannot activate the transcription of related genes, which decrease the level of insulin by affecting beta cell proliferation, apoptosis and the secretion of insulin and increase the insulin resistance in the target tissue of insulin, leading to the development of PTDM.

Key words: Tacrolimus, Diabetes, Calcineurin/NFATc signaling

中图分类号:

R587
R969

汪江林, 左笑丛, 杨梦, 周凌云. 钙调神经磷酸酶/NFATc信号通路介导他克莫司诱导移植后糖尿病的研究进展[J]. 中国临床药理学与治疗学, 2014, 19(1): 74-81.

WANG Jiang-lin, ZUO Xiao-cong, YANG Meng, ZHOU Ling-yun. Advances in the study of post-transplantation diabetes mellitus resulting from tacrolimus via calcineurin/NFAT signaling[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2014, 19(1): 74-81.

参考文献

[1] Gomes MB, Cobas RA. Post-transplant diabetes mellitus[J]. Diabetol Metab Syndr, 2009, 1(1): 14.
[2] 余爱荣, 范星, 刘慧明, 等. 中国肾移植患者钙蛋白酶10基因多态性与移植后糖尿病的相关性研究[J]. 中国临床药理学与治疗学, 2012, 17(8): 901-906.
[3] Fernandez-Fresnedo G, Escallada R, de Francisco AL, et al. Posttransplant diabetes is a cardiovascular risk factor in renal transplant patients[J].Transplant Proc, 2003, 35(2): 700.
[4] Shivaswamy V, McClure M, Passer J, et al. Hyperglycemia induced by tacrolimus and sirolimus is reversible in normal sprague-dawley rats[J]. Endocrine, 2010, 37(3): 489-496.
[5] Al-Ghareeb SM, El-Agroudy AE, Al AS, et al. Risk factors and outcomes of new-onset diabetes after transplant: single-centre experience[J]. Exp Clin Transplant, 2012, 10(5): 458-465.
[6] Gnatta D, Keitel E, Heineck I, et al. Use of tacrolimus and the development of posttransplant diabetes mellitus: a Brazilian single-center, observational study[J]. Transplant Proc, 2010, 42(2): 475-478.
[7] Borda B, Lengyel C, Szederkenyi E, et al. Post-transplant diabetes mellitus-risk factors and effects on the function and morphology of the allograft[J]. Acta Physiol Hung, 2012, 99(2): 206-215.
[8] Rusnak F, Mertz P. Calcineurin: form and function[J]. Physiol Rev, 2000, 80(4): 1483-1521.
[9] Ke H, Huai Q. Structures of calcineurin and its complexes with immunophilins-immunosuppressants [J]. Biochem Biophys Res Commun, 2003, 311(4): 1095-1102.
[10] Herzig S, Neumann J. Effects of serine/threonine protein phosphatases on ion channels in excitable membranes[J]. Physiol Rev, 2000, 80(1): 173-210.
[11] Li HC. Activation of brain calcineurin phosphatase towards nonprotein phosphoesters by Ca²⁺, calmodulin, and Mg²⁺[J]. J Biol Chem, 1984, 259(14): 8801-8807.
[12] Heit JJ, Apelqvist AA, Gu X, et al. Calcineurin/NFAT signalling regulates pancreatic beta-cell growth and function[J]. Nature, 2006, 443(7109): 345-349.
[13] Park S, Uesugi M, Verdine GL. A second calcineurin binding site on the NFAT regulatory domain[J]. Proc Natl Acad Sci USA, 2000, 97(13): 7130-7135.
[14] Ruff VA, Leach KL. Direct demonstration of NFATp dephosphorylation and nuclear localization in activated HT-2 cells using a specific NFATp polyclonal antibody[J]. J Biol Chem, 1995, 270(38): 22602- 22607.
[15] Marchetti P, Bugliani M, Boggi U, et al. The pancreatic beta cells in human type 2 diabetes[J]. Adv Exp Med Biol, 2012, 771: 288-309.
[16] Cerf ME. Beta cell dysfunction and insulin resistance[J]. Front Endocrinol (Lausanne), 2013, 4: 37.
[17] Zelle DM, Corpeleijn E, Deinum J, et al. Pancreatic beta-cell dysfunction and risk of new-onset diabetes after kidney transplantation[J]. Diabetes Care, 2013, 36(7): 1926-1932.
[18] Heit JJ. Calcineurin/NFAT signaling in the beta-cell: from diabetes to new therapeutics[J]. Bioessays, 2007, 29(10): 1011-1021.
[19] Chin ER, Olson EN, Richardson JA, et al. A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type[J]. Genes Dev, 1998, 12(16): 2499-2509.
[20] Martins KJ, St-Louis M, Murdoch GK, et al. Nitric oxide synthase inhibition prevents activity-induced calcineurin-NFATc1 signalling and fast-to-slow skeletal muscle fibre type conversions[J]. J Physiol, 2012, 590(Pt 6): 1427-1442.
[21] Heit JJ, Karnik SK, Kim SK. Intrinsic regulators of pancreatic beta-cell proliferation[J]. Annu Rev Cell Dev Biol, 2006, 22: 311-338.
[22] Rane SG, Dubus P, Mettus RV, et al. Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia[J]. Nat Genet, 1999, 22(1): 44-52.
[23] Song WJ, Schreiber WE, Zhong E, et al. Exendin-4 stimulation of cyclin A2 in beta-cell proliferation [J]. Diabetes, 2008, 57(9): 2371-2381.
[24] Wakae-Takada N, Xuan S, Watanabe K, et al. Molecular basis for the regulation of islet beta cell mass in mice: the role of E-cadherin[J]. Diabetologia, 2013, 56(4): 856-866.
[25] Chen S, Shimoda M, Chen J, et al. Transient overexpression of cyclin D2/CDK4/GLP1 genes induces proliferation and differentiation of adult pancreatic progenitors and mediates islet regeneration[J]. Cell Cycle, 2012, 11(4): 695-705.
[26] Cui W, De Jesus K, Zhao H, et al. Overexpression of Reg3alpha increases cell growth and the levels of cyclin D1 and CDK4 in insulinoma cells[J]. Growth Factors, 2009, 27(3): 195-202.
[27] Davis DB, Lavine JA, Suhonen JI, et al. FoxM1 is up-regulated by obesity and stimulates beta-cell proliferation[J]. Mol Endocrinol, 2010, 24(9): 1822-1834.
[28] Goodyer WR, Gu X, Liu Y, et al. Neonatal beta cell development in mice and humans is regulated by calcineurin/NFAT[J]. Dev Cell, 2012, 23(1): 21-34.
[29] Soleimanpour SA, Crutchlow MF, Ferrari AM, et al. Calcineurin signaling regulates human islet {beta}-cell survival[J]. J Biol Chem, 2010, 285(51): 40050-40059.
[30] Rostambeigi N, Lanza IR, Dzeja PP, et al. Unique cellular and mitochondrial defects mediate FK506-induced islet beta-cell dysfunction[J]. Transplantation, 2011, 91(6): 615-623.
[31] Li QY, Li F, Sun JH, et al. Mechanisms of diabetes mellitus induced with FK506 in SD rats models[J]. Immunopharmacol Immunotoxicol, 2009, 31(4): 675-681.
[32] Bugliani M, Masini M, Liechti R, et al. The direct effects of tacrolimus and cyclosporin A on isolated human islets: A functional, survival and gene expression study[J]. Islets, 2009, 1(2): 106-110.
[33] Briaud I, Dickson LM, Lingohr MK, et al. Insulin receptor substrate-2 proteasomal degradation mediated by a mammalian target of rapamycin (mTOR)-induced negative feedback down-regulates protein kinase B-mediated signaling pathway in beta-cells[J]. J Biol Chem, 2005, 280(3): 2282-2293.
[34] Kubota N, Tobe K, Terauchi Y, et al. Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia[J]. Diabetes, 2000, 49(11): 1880-1889.
[35] Demozay D, Tsunekawa S, Briaud I, et al. Specific glucose-induced control of insulin receptor substrate-2 expression is mediated via Ca²⁺-dependent calcineurin/NFAT signaling in primary pancreatic islet beta-cells[J]. Diabetes, 2011, 60(11): 2892-2902.
[36] Johnson JD, Ao Z, Ao P, et al. Different effects of FK506, rapamycin, and mycophenolate mofetil on glucose-stimulated insulin release and apoptosis in human islets[J]. Cell Transplant, 2009, 18(8): 833-845.
[37] Redmon JB, Olson LK, Armstrong MB, et al. Effects of tacrolimus (FK506) on human insulin gene expression, insulin mRNA levels, and insulin secretion in HIT-T15 cells[J]. J Clin Invest, 1996, 98(12): 2786-2793.
[38] Takemitsu H, Yamamoto I, Lee P, et al. cDNA cloning and mRNA expression of canine pancreatic and duodenum homeobox 1 (Pdx-1)[J]. Res Vet Sci, 2012, 93(2): 770-775.
[39] Aguayo-Mazzucato C, Zavacki AM, Marinelarena A, et al. Thyroid hormone promotes postnatal rat pancreatic beta-cell development and glucose-responsive insulin secretion through MAFA[J]. Diabetes, 2013, 62(5): 1569-1580.
[40] Kim JW, You YH, Jung S, et al. miRNA-30a-5p-mediated silencing of Beta2/NeuroD expression is an important initial event of glucotoxicity-induced beta cell dysfunction in rodent models[J]. Diabetologia, 2013, 56(4): 847-855.
[41] Radu RG, Fujimoto S, Mukai E, et al. Tacrolimus suppresses glucose-induced insulin release from pancreatic islets by reducing glucokinase activity[J]. Am J Physiol Endocrinol Metab, 2005, 288(2): E365-E371.
[42] Rauch MC, San MA, Ojeda D, et al. Tacrolimus causes a blockage of protein secretion which reinforces its immunosuppressive activity and also explains some of its toxic side-effects[J]. Transpl Immunol, 2009, 22(1/2): 72-81.
[43] Ozbay LA, Smidt K, Mortensen DM, et al. Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in INS-1E beta-cells[J]. Br J Pharmacol, 2011, 162(1): 136-146.
[44] Malinowski M, Pratschke J, Lock J, et al. Effect of tacrolimus dosing on glucose metabolism in an experimental rat model[J]. Ann Transplant, 2010, 15(3): 60-65.
[45] Duijnhoven EM, Boots JM, Christiaans MH, et al. Influence of tacrolimus on glucose metabolism before and after renal transplantation: a prospective study[J]. J Am Soc Nephrol, 2001, 12(3): 583-588.
[46] Tsuchiya T, Ishida K, Ito S, et al. Effect of conversion from twice-daily to once-daily tacrolimus on glucose intolerance in stable kidney transplant recipients[J]. Transplant Proc, 2012, 44(1): 118-120.
[47] Larsen JL, Bennett RG, Burkman T, et al. Tacrolimus and sirolimus cause insulin resistance in normal sprague dawley rats[J]. Transplantation, 2006, 82(4): 466-470.
[48] Chakkera HA, Mandarino LJ. Calcineurin inhibition and new-onset diabetes mellitus after transplantation[J]. Transplantation, 2013, 95(5): 647-652.
[49] Ozbay LA, Moller N, Juhl C, et al. The impact of calcineurin inhibitors on insulin sensitivity and insulin secretion: a randomized crossover trial in uraemic patients[J]. Diabet Med, 2012, 29(12): e440-e444.
[50] Wyzgal J, Paczek L, Sanko-Resmer J, et al. Insulin resistance in kidney allograft recipients treated with calcineurin inhibitors[J]. Ann Transplant, 2007, 12(2): 26-29.
[51] Mallinson J, Meissner J, Chang KC. Chapter 2. Calcineurin signaling and the slow oxidative skeletal muscle fiber type[J]. Int Rev Cell Mol Biol, 2009, 277: 67-101.
[52] Calabria E, Ciciliot S, Moretti I, et al. NFAT isoforms control activity-dependent muscle fiber type specification[J]. Proc Natl Acad Sci USA, 2009, 106(32): 13335-13340.
[53] McCullagh KJ, Calabria E, Pallafacchina G, et al. NFAT is a nerve activity sensor in skeletal muscle and controls activity-dependent myosin switching[J]. Proc Natl Acad Sci USA, 2004, 101(29): 10590- 10595.
[54] Meissner JD, Umeda PK, Chang KC, et al. Activation of the beta myosin heavy chain promoter by MEF-2D, MyoD, p300, and the calcineurin/NFATc1 pathway[J]. J Cell Physiol, 2007, 211(1): 138-148.
[55] Kubis HP, Hanke N, Scheibe RJ, et al. Ca²⁺ transients activate calcineurin/NFATc1 and initiate fast-to-slow transformation in a primary skeletal muscle culture[J]. Am J Physiol Cell Physiol, 2003, 285(1): C56-C63.
[56] Miyazaki M, Hitomi Y, Kizaki T, et al. Calcineurin-mediated slow-type fiber expression and growth in reloading condition[J]. Med Sci Sports Exerc, 2006, 38(6): 1065-1072.
[57] Escribano O, Guillen C, Nevado C, et al. Beta-cell hyperplasia induced by hepatic insulin resistance: role of a liver-pancreas endocrine axis through insulin receptor A isoform[J]. Diabetes, 2009, 58(4): 820-828.