钠钙交换体与肾缺血再灌注损伤

doi:10.12092/j.issn.1009-2501.2019.03.020

摘要/Abstract

摘要：

钠钙交换体（sodium calcium exchanger,NCX）是一种广泛分布于膜性结构（细胞质膜、线粒体膜和分泌小泡膜等）上的阳离子转运蛋白，具有前向模式和反向模式。通过这种双向模式，可以对胞质内的Ca2+浓度进行快速精准的调节，继而影响细胞的一系列生理活动。而肾缺血再灌注时，NCX反向模式的异常激活可介导细胞Ca2+超载，进而触发一系列有害代谢反应导致细胞损伤和死亡。目前，选择性抑制NCX反向模式的苯氧基衍生物得到了较多研究，并成为治疗肾缺血再灌注损伤的新药物靶点。

关键词: 钠钙交换体, 肾缺血再灌注, 钙超载, 苯氧基衍生物

Abstract:

Sodium calcium exchanger (NCX), which is widely expressed in the plasma membrane, mitochondrial membrane and secretory vesicles in diverse kinds of cells, belongs to a type of cation translocators. NCX works in two modes, the forward mode and reverse mode. Exactly through the two-way modes, NCX can regulate intracellular Ca2+ concentration fleetly and accurately, and plays a critical role in a series of physiological processes. However, abnormal activation of the reverse mode of NCX plays a vital role in renal ischemia reperfusion injury, which can mediate the overload of cytoplasmic Ca2+, then triggers a series of harmful metabolic reactions that led to cell injury and death. Currently, phenoxyl derivatives that selectively inhibit the reverse mode of NCX have been extensively studied and become new drug targets for the treatment of renal ischemia reperfusion injury.

Key words: sodium calcium exchanger, renal ischemia reperfusion injury, calcium overload, phenoxyl derivatives

中图分类号:

R692.9

陈朝虎，庄华，姚志强，汉大黎，常成，马忠义，孔祥斌，曹金龙，李攀，田俊强. 钠钙交换体与肾缺血再灌注损伤[J]. 中国临床药理学与治疗学, 2019, 24(3): 355-360.

CHEN Chaohu, ZHUANG Hua, YAO Zhiqiang, HAN Dali, CHANG Cheng, MA Zhongyi, KONG Xiangbing, CAO Jinlong, LI Pan, TIAN Junqiang. Sodium calcium exchanger and renal ischemia reperfusion injury[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(3): 355-360.

参考文献

［1］Roome CJ, Power EM, Empson RM. Transient reversal of the sodium/calcium exchanger boosts presynaptic calcium and synaptic transmission at a cerebellar synapse［J］. J Neurophysiol, 2013, 109(6): 1669-1680.
［2］Shenoda B. The Role of Na+/Ca2+ exchanger subtypes in neuronal ischemic injury［J］. Transl Stroke Res, 2015, 6(3): 181-190.
［3］Wang M, Tan J, Miao Y, et al. Role of Ca2+ and ion channels in the regulation of apoptosis under hypoxia［J］. Histol Histopathol, 2018, 33(3): 237-246.
［4］O'Kane D, Gibson L, May CN, et al. Zinc preconditioning protects against renal ischaemia reperfusion injury in a preclinical sheep large animal model［J］. Biometals, 2018, 31(5): 821-834.
［5］Fu Y, Tang C, Cai J, et al. Rodent models of AKI-CKD transition［J］. Am J Physiol-Renal Physiol, 2018, 315(4): F1098-F106.
［6］He C, O'Halloran DM. Analysis of the Na+/Ca2+ Exchanger gene family within the phylum nematoda［J］. PloS one, 2014, 9(11): e112841.
［7］Roome CJ, Knoepfel T, Empson RM. Functional contributions of the plasma membrane calcium ATPase and the sodium-calcium exchanger at mouse parallel fibre to Purkinje neuron synapses［J］. Pflu Archiv-Eur J Physiol, 2013, 465(2): 319-331.
［8］Palty R, Hershfinkel M, Sekler I. Molecular identity and functional properties of the mitochondrial Na+/Ca2+ exchanger［J］. J Biol Chem, 2012, 287(38): 31650-31657.
［9］Ikeda K, Nakajima T, Yamamoto Y, et al. Roles of transient receptor potential canonical (TRPC) channels and reverse-mode Na+/Ca2+ exchanger on cell proliferation in human cardiac fibroblasts: effects of transforming growth factor beta 1［J］. Cell Calcium, 2013, 54(3): 213-225.
［10］Khananshvili D. The SLC8 gene family of sodium-calcium exchangers (NCX) - Structure, function, and regulation in health and disease［J］. Mol Asp Med, 2013, 34(2/3): 220-235.
［11］John S, Kim B, Olcese R, et al. Molecular determinants of pH regulation in the cardiac Na+/Ca2+ exchanger［J］. J Gene Physiol, 2018, 150(2): 245-257.
［12］Esrafili MD, Asadollahi S. The enhancing effect of a cation-pi interaction on the cooperativity of halogen bonds: A computational study［J］. J Mol Grap Mod, 2017, 73: 200-207.
［13］Chang PC, Lu YY, Lee HL, et al. Paradoxical effects of sodium-calcium exchanger inhibition on torsade de pointes and early afterdepolarization in a heart failure rabbit model［J］. J Cardiovas Pharmacol, 2018, 72(2): 97-105.
［14］Bogeholz N, Schulte JS, Kaese S, et al. The effects of SEA0400 on Ca2+ transient amplitude and proarrhythmia depend on the Na+/Ca2+ exchanger expression level in murine models［J］. Front Pharmacol, 2017, 8: 649.
［15］Sherkhane P, Kapfhammer JP. Chronic pharmacological blockade of the Na+/Ca2+ exchanger modulates the growth and development of the Purkinje cell dendritic arbor in mouse cerebellar slice cultures［J］. Euro J Neuro, 2017, 46(5): 2108-2120.
［16］Su JJ, Qi GY, Dang XZ, et al. Progress in the physiological and pathophysiological functions of sodium calcium exchangers［J］. Shengli Xuebao, 2014, 66(2): 241-251.
［17］Parnis J, Montana V, Delgado-Martinez I, et al. Mitochondrial exchanger NCLX plays a major role in the intracellular Ca2+ signaling, gliotransmission, and proliferation of astrocytes［J］. J Neuro, 2013, 33(17): 7206-7219.
［18］Machado Berger RC, Benetti A, Costa Girardi AC, et al. Influence of long-term salt diets on cardiac Ca2+ handling and contractility proteins in hypertensive rats［J］. Am J Hyp, 2018, 31(6): 726-734.
［19］Liu B, Yang L, Zhang B, et al. NF-kappa B-dependent upregulation of NCX1 induced by angiotensin II contributes to calcium influx in rat aortic smooth muscle cells［J］. Cana J Cardiol, 2016, 32(11): 1356.
［20］Mori Y, Tomonaga D, Kalashnikova A, et al. Effects of 3,3', 5-triiodothyronine on microglial functions［J］. Glia, 2015, 63(5): 906-920.
［21］Sunkaria A, Bhardwaj S, Halder A, et al. Migration and phagocytic ability of activated microglia during post-natal development is mediated by calcium-dependent purinergic signalling［J］. Mol Neurobiol, 2016, 53(2): 944-954.
［22］Fu C, Hao J, Zeng M, et al. Modulation of late sodium current by Ca2+-calmodulin-dependent protein kinase II, protein kinase C and Ca2+ during hypoxia in rabbit ventricular myocytes［J］. Exp Physiol, 2017, 102(7): 818-834.
［23］Kortus S, Srinivasan C, Forostyak O, et al. Sodium-calcium exchanger and R-type Ca2+ channels mediate spontaneous Ca2+ (i) oscillations in magnocellular neurones of the rat supraoptic nucleus［J］. Cell Calcium, 2016, 59(6): 289-298.
［24］Khananshvili D. Sodium-calcium exchangers (NCX): molecular hallmarks underlying the tissue-specific and systemic functions［J］. Pfl Archiv-Eur J Physiol, 2014, 466(1): 43-60.
［25］Yuan J, Yuan C, Xie M, et al. The intracellular loop of the Na+/Ca2+ exchanger contains an "awareness ribbon"-shaped two-helix bundle domain［J］. Biochem, 2018, 57(34): 5096-5104.
［26］Bode K, O'Halloran DM. NCX-DB: a unified resource for integrative analysis of the sodium calcium exchanger super-family［J］. Bmc Neurosci, 2018, 19(1): 19.
［27］Gu L, Tao Y, Chen C, et al. Initiation of the inflammatory response after renal ischemia/reperfusion injury during renal transplantation［J］. Int Urol Nephrol, 2018, 50(11): 2027-2035.
［28］Kalogeris T, Baines CP, Krenz M, et al. Ischemia/reperfusion［J］. Compre Physiol, 2017, 7(1): 113-170.
［29］Bano D, Nicotera P. Ca2+ signals and neuronal death in brain ischemia［J］. Stroke, 2007, 38(2): 674-676.
［30］Ladilov Y, Haffner S, Balser-Schafer C, et al. Cardioprotective effects of KB-R7943: a novel inhibitor of the reverse mode of Na+/Ca2+ exchanger［J］. Am J Physiol-Heart Circul Physiol, 1999, 276(6): H1868-H76.
［31］Yamashita J, Itoh M, Kuro T, et al. Pre-or post-ischemic treatment with a novel Na+/Ca2+ exchange inhibitor, KB-R7943, shows renal protective effects in rats with ischemic acute renal failure (retraction of vol 296, pg 412, 2001) ［J］. J Pharmacol Exp Thera, 2014, 349(2): 344.
［32］Tu J, Lu L, Cai W, et al. cAMP/protein kinase A activates cystic fibrosis transmembrane conductance regulator for ATP release from rat skeletal muscle during low pH or contractions［J］. PloS One, 2012, 7(11): e50157.
［33］Hernandez-Ojeda M, Urena-Guerrero ME, Gutierrez-Barajas PE, et al. KB-R7943 reduces 4-aminopyridine-induced epileptiform activity in adult rats after neuronal damage induced by neonatal monosodium glutamate treatment［J］. J Bio Sci, 2017, 24(1): 27.
［34］Iwamoto T, Kita S, Uehara A, et al. Molecular determinants of Na+/Ca2+ exchange (NCX1) inhibition by SEA0400［J］. J Biol Chem, 2004, 279(9): 7544-7553.
［35］Iwamoto T, Inoue Y, Ito K, et al. The exchanger inhibitory peptide region-dependent inhibition of Na+/Ca2+ exchange by SN-6 2- 4-(4-nitrobenzyloxy)benzyl thiazolidine-4-carboxylic acid ethyl ester, a novel benzyloxyphenyl derivative［J］. Mol Pharmacol, 2004, 66(1): 45-55.
［36］Iwamoto T, Kita S. YM-244769, a novel Na+/Ca2+ exchange inhibitor that preferentially inhibits NCX3, efficiently protects against hypoxia/reoxygenation-induced SH-SY5Y neuronal cell damage［J］. Mol Pharmacol, 2006, 70(6): 2075-2083.
［37］Gotoh Y, Kita S, Fujii M, et al. Genetic knockout and pharmacologic inhibition of NCX2 cause natriuresis and hypercalciuria［J］. Bio Biophy Res Commu, 2015, 456(2): 670-675.
［38］Bouchard R, Omelchenko A, Le HD, et al. Effects of SEA0400 on mutant NCX1.1 Na+/Ca2+ exchangers with altered ionic regulation［J］. Mol Pharmacol, 2004, 65(3): 802-810.
［39］Goto Y, Ogata M, Kita S, et al. YM-244769, a novel Na+/Ca2+ exchange inhibitor, efficiently improves ischemia/reperfusion-induced renal injury［J］. Bio J, 2012, 102(3): 662A-663A.
［40］Yamashita J, Kita S, Iwamoto T, et al. Attenuation of ischemia/reperfusion-induced renal injury in mice deficient in Na+/Ca2+ Exchange［J］. J Pharmacol Exp Ther, 2003, 304(1): 284-293.
［41］Ogata M, Iwamoto T, Tazawa N, et al. A novel and selective Na+/Ca2+ exchange inhibitor, SEA0400, improves ischemia/reperfusion-induced renal injury［J］. Euro J Pharmacol, 2003, 478(2/3): 187-98.
［42］Schroder UH, Breder J, Sabelhaus CF, et al. The novel Na+/Ca2+ exchange inhibitor KB-R7943 protects CA1 neurons in rat hippocampal slices against hypoxic/hypoglycemic Injury［J］. Neuropharmacol, 1999, 38(2): 319-321.
［43］Wakimoto K, Kobayashi K, Kuro-o M, et al. Targeted disruption of Na+/Ca2+ exchange gene leads to cardiomyocyte apoptosis and defects in heartbeat［J］. J Biol Chem, 2000, 275(47): 36991-36998.
［44］Hamming KSC, Soliman D, Webster NJ, et al. Inhibition of beta-cell sodium-calcium exchange enhances glucose-dependent elevations in cytoplasmic calcium and insulin secretion［J］. Diabetes, 2010, 59(7): 1686-1693.
［45］Takai N, Yamada A, Muraki K, et al. KB-R7943 reveals possible involvement of Na+/Ca2+ exchange in elevation of intracellular Ca2+ in rat carotid arterial myocytes［J］. J Sm Mus Res, 2004, 40(1): 35-42.
［46］Yamashita J, Itoh M, Kuro T, et al. Pre- or post-ischemic treatment with a novel Na+/Ca2+ Exchange inhibitor, KB-R7943, shows renal protective effects in rats with ischemic acute renal failure［J］. J Pharmacol Exp Ther, 2001, 286(2): 412-419.
［47］Kuro T, Kobayashi Y, Takaoka M, et al. Protective effect of KB-R7943, a novel Na+/Ca2+ exchange inhibitor, on ischemic acute renal failure in rats［J］. Jpn J Pharmacol, 1999, 81(2): 247-251.
［48］Wiczer BM, Marcu R, Hawkins BJ. KB-R7943, a plasma membrane Na+/Ca2+ exchange inhibitor, blocks opening of the mitochondrial permeability transition pore［J］. Bio Biophy Res Commu, 2014, 444(1): 44-49.
［49］Abramov AY, Duchen MR. Actions of ionomycin, 4-BrA23187 and a novel electrogenic Ca(2+) ionophore on mitochondria in intact cells［J］. Cell Calcium, 2003, 33(2): 101-112.
［50］Ogata M, Iwamoto T, Tazawa N, et al. A novel and selective Na+/Ca2+ Exchange inhibitor, SEA0400, improves ischemia/reperfusion-induced renal injury［J］. Eur J Pharmacol, 2003, 478(2/3): 187-198.
［51］Yonehana T, Gemba M. Ameliorative effect of adenosine on hypoxia-reoxygenation injury in LLC-PK1, a porcine kidney cell line［J］. Jpn J Pharmacol, 1999, 80(2): 163-167.
［52］Gotoh Y, Ogata M, Kita S, et al. YM-244769, a novel Na+/Ca2+ exchange inhibitor, efficiently improves ischemia/reperfusion-induced renal injury (vol 70, pg 2075, 2006) ［J］. Biophy J, 2012, 102(6): 1468.

[1]	文继月，陈志武. 黄蜀葵花总黄酮对海马神经元缺氧复氧损伤的保护作用[J]. 中国临床药理学与治疗学, 2017, 22(4): 367-372.
[2]	曾雯君, 沈磊, 吴玉林. 钠钙交换体及其抑制剂在脑缺血中的作用[J]. 中国临床药理学与治疗学, 2009, 14(2): 237-240.
[3]	沈磊, 吴玉林. 钠钙交换体及其抑制剂在心律失常中的作用[J]. 中国临床药理学与治疗学, 2006, 11(6): 610-613.
[4]	孙艳玲, 刘先义. 参附注射液对大鼠肾缺血再灌注损伤的防治作用[J]. 中国临床药理学与治疗学, 2005, 10(8): 943-946.
[5]	霍展样, 牛桂萍, 刘晓丽. 川芎嗪对小鼠急性肾缺血再灌注损伤的保护作用研究[J]. 中国临床药理学与治疗学, 2004, 9(2): 230-233.
[6]	何丽娜, 杨军, 何素冰. 赤芍总甙对氯化钾及N-甲基-D-门冬氨酸诱导的PC12细胞钙超载损伤的保护作用[J]. 中国临床药理学与治疗学, 2000, 5(2): 120-122.