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中华重症医学电子杂志 ›› 2017, Vol. 03 ›› Issue (03) : 231 -237. doi: 10.3877/cma.j.issn.2096-1537.2017.03.015

所属专题: 文献

综述

"铁死亡"在横纹肌溶解导致急性肾损伤中的研究现状
吴明1, 苏磊2,()   
  1. 1. 518035 深圳市第二人民医院重症医学科
    2. 508010 广州军区广州总医院重症医学科
  • 收稿日期:2016-12-28 出版日期:2017-08-28
  • 通信作者: 苏磊
  • 基金资助:
    国家自然科学基金(81671896); 广东省医学科学技术研究基金(A2016353); 广东省深圳市科技创新委项目(JCY20150330102401099、JCYJ20160425103130218)

Current research situation of ferroptosis in rhabdomyolysis-induced acute kidney injury

Ming Wu1, Lei Su2,()   

  1. 1. Department of Critical Care Medicine of The Second People′s Hospital of ShenZhen, Shenzhen 518035, China
  • Received:2016-12-28 Published:2017-08-28
  • Corresponding author: Lei Su
  • About author:
    Corresponding author: Su Lei, Email:
引用本文:

吴明, 苏磊. "铁死亡"在横纹肌溶解导致急性肾损伤中的研究现状[J]. 中华重症医学电子杂志, 2017, 03(03): 231-237.

Ming Wu, Lei Su. Current research situation of ferroptosis in rhabdomyolysis-induced acute kidney injury[J]. Chinese Journal of Critical Care & Intensive Care Medicine(Electronic Edition), 2017, 03(03): 231-237.

肌肉的直接创伤,剧烈运动及肌肉代谢改变,化学、物理或生物制剂的毒性作用以及遗传等因素均可导致横纹肌溶解(RM)。以往发现大量肌红蛋白引起肾小管堵塞、肾血管收缩、触发剧烈炎症反应、诱导细胞凋亡是横纹肌溶解致肾损伤的主要机制。肌红蛋白介导肾小管上皮细胞发生脂质过氧化与谷氨酸代谢密切相关,通过多种信号分子介导近端肾小管铁死亡(ferroptosis),铁死亡是肌红蛋白诱导急性肾损伤(AKI)更为重要的机制。铁螯合剂,即去铁胺可减轻横纹肌溶解诱导的急性肾损伤,因其水溶性强,具有一定的肾毒性,限制了其在临床上的应用。去铁胺通过结合铁金刚烷衍生物,增加脂溶性,减少细胞毒性及保留抗炎和抗氧化能力。来自植物木蝴蝶等的黄芩素,具有抗细胞铁死亡能力,可能作为铁死亡相关组织损伤的治疗。高分子截留血液滤过(HCO)可以清除肌红蛋白,已成为横纹肌溶解导致急性肾损伤肾替代治疗优先选择的模式。

Rhabdomyolysis (RM) can be induced by severe muscles injury, strenuous exercise, intrinsic metabolic of muscle cells, and the toxic effects of chemical, physical, or biological agents. Myoglobin induced tubular obstruction, renal vasoconstriction, inflammation and apoptosis play a key role in rhabdomyolysis-associated kidney damage. Lipid peroxidation of renal tubular epithelial cells mediated by myoglobin is closely related to glutamate metabolism, whichinduce renal proximal tubular ferroptosis through a variety of signal molecules. Ferroptosis plays a key role in myoglobin induced acute renal injury (AKI). Desferrioxamine is an iron chelator that inhibits lipid peroxidation by reducing myoglobin-derived acute kidney injury. However, it is limited in clinical practice because of its hydrophilic properties and direct nephrotoxic effects.. Deferoxamine conjugated to adamantyl derivatives, which obtains lipophilic capacity. Baicalein, a kind of traditional Chinese medicine, can enhance cellular anti-ferroptosis capacity, which may be a potential therapeutic agent for ferroptosis-associated tissue injury. Myoglobin can be removed by high cut off hemofiltration (HCO), which has become the preferred treatment mode of renal replacement of RM-induced AKI.

图1 横纹肌溶解的分子机制图
图2 肌红蛋白诱导急性肾衰的机制
图3 铁代谢与铁死亡模式图
1
Bagley WH, Yang H, Shah KH. Rhabdomyolysis[J]. Intern Emerg Med, 2007, 2(3): 210-218.
2
Sauret JM, Marinides G, Wang GK. Rhabdomyolysis[J]. Am Fam Physician, 2002, 65(5): 907-912.
3
Holt SG, Moore KP. Pathogenesis and treatment of renal dysfunction in rhabdomyolysis[J]. Intensive Care Med, 2001, 27(5): 803-811.
4
Alpers JP, Jones LK Jr. Natural history of exertional rhabdomyolysis: a population-based analysis[J]. Muscle Nerve, 2010, 42(4): 487-491.
5
Perreault S, Birca A, Piper D, et al. Transient creatine phosphokinase elevations in children: a single-center experience[J]. J Pediatr, 2011, 159(4): 682-685.
6
Mackay MT, Kornberg AJ, Shield LK, et al. Benign acute childhood myositis: laboratory and clinical features[J]. Neurology, 1999, 53(9): 2127-2131.
7
Zimmerman JL, Shen MC. Rhabdomyolysis[J]. Chest, 2013, 144(3): 1058-1065.
8
Wen X, Peng Z, Kellum JA. Pathogenesis of acute kidney injury: effects of remote tissue damage on the kidney[J]. Contrib Nephrol, 2011, 174: 129-137.
9
Belliere J, Casemayou A, Ducasse L, et al. Specific macrophage subtypes influence the progression of rhabdomyolysis-induced kidney injury[J]. J Am Soc Nephrol, 2015, 26(6): 1363-1377.
10
de Meijer AR, Fikkers BG, de Keijzer MH, et al. Serum creatine kinase as predictor of clinical course in rhabdomyolysis: a 5-year intensive care survey[J]. Intensive Care Med, 2003, 29(7): 1121-1125.
11
Coca SG, Singanamala S, Parikh CR. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis[J]. Kidney Int, 2012, 81(5): 442-448.
12
Panizo N, Rubio-Navarro A, Amaro-Villalobos JM, et al. Molecular Mechanisms and Novel Therapeutic Approaches to Rhabdomyolysis-Induced Acute Kidney Injury[J]. Kidney Blood Press Res, 2015, 40(5): 520-532.
13
Brown CV, Rhee P, Chan L, et al. Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference? [J]. J Trauma, 2004, 56(6): 1191-1196.
14
Mulay SR, Kumar SV, Lech M, et al. How Kidney Cell Death Induces Renal Necroinflammation[J]. Semin Nephrol, 2016, 36(3): 162-173.
15
Moreno JA, Martín-Cleary C, Gutiérrez E, et al. AKI associated with macroscopic glomerular hematuria: clinical and pathophysiologic consequences[J]. Clin J Am Soc Nephrol, 2012, 7(1): 175-184.
16
Jang HR, Rabb H. The innate immune response in ischemic acute kidney injury[J]. Clin Immunol, 2009, 130(1): 41-50.
17
Gonzalez-Michaca L, Farrugia G, Croatt AJ, et al. Heme: a determinant of life and death in renal tubular epithelial cells[J]. Am J Physiol Renal Physiol, 2004, 286(2): F370-377.
18
Moreno JA, Martín-Cleary C, Gutiérrez E, et al. Haematuria: the forgotten CKD factor? [J]. Nephrol Dial Transplant, 2012, 27(1): 28-34.
19
Wagener FA, Feldman E, de Witte T, et al. Heme induces the expression of adhesion molecules ICAM-1, VCAM-1, and E selectin in vascular endothelial cells[J]. Proc Soc Exp Biol Med, 1997, 216(3): 456-463.
20
Komada T, Usui F, Kawashima A, et al. Role of NLRP3 Inflammasomes for Rhabdomyolysis-induced Acute Kidney Injury[J]. Sci Rep, 2015, 5: 10901.
21
Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell, 2012, 149(5): 1060-1072.
22
Xie Y, Hou W, Song X, et al. Ferroptosis: process and function[J]. Cell Death Differ, 2016, 23(3): 369-379.
23
Skouta R, Dixon SJ, Wang J, et al. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models[J]. J Am Chem Soc, 2014, 136(12): 4551-4556.
24
Chatzizisis YS, Misirli G, Hatzitolios AI, et al. The syndrome of rhabdomyolysis: complications and treatment[J]. Eur J Intern Med, 2008, 19(8): 568-574.
25
Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury[J]. N Engl J Med, 2009, 361(1): 62-72.
26
Zarjou A, Bolisetty S, Joseph R, et al. Proximal tubule H-ferritin mediates iron trafficking in acute kidney injury[J]. J Clin Invest, 2013, 123(10): 4423-4434.
27
Dixon SJ, Stockwell BR. The role of iron and reactive oxygen species in cell death[J]. Nat Chem Biol, 2014, 10(1): 9-17.
28
Fähling M, Mathia S, Paliege A, et al. Tubular von Hippel-Lindau knockout protects against rhabdomyolysis-induced AKI[J]. J Am Soc Nephrol, 2013, 24(11): 1806-1819.
29
Yagoda N, von Rechenberg M, Zaganjor E, et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels[J]. Nature, 2007, 447(7146): 864-868.
30
Sogabe K, Roeser NF, Venkatachalam MA, et al. Differential cytoprotection by glycine against oxidant damage to proximal tubule cells[J]. Kidney Int, 1996, 50(3): 845-854.
31
Gao M, Monian P, Quadri N, et al. Glutaminolysis and Transferrin Regulate Ferroptosis[J]. Mol Cell, 2015, 59(2): 298-308.
32
Yang WS, SriRamaratnam R, Welsch ME, et al. Regulation of ferroptotic cancer cell death by GPX4[J]. Cell, 2014, 156(1-2): 317-331.
33
Gao M, Monian P, Jiang X. Metabolism and iron signaling in ferroptotic cell death[J]. Oncotarget, 2015, 6(34): 35145-35146.
34
Jiang L, Kon N, Li T, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature, 2015, 520(7545): 57-62.
35
Hayano M, Yang WS, Corn CK, et al. Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation[J]. Cell Death Differ, 2016, 23(2): 270-278.
36
Herbison CE, Thorstensen K, Chua AC, et al. The role of transferrin receptor 1 and 2 in transferrin-bound iron uptake in human hepatoma cells[J]. Am J Physiol Cell Physiol, 2009, 297(6): C1567-C1575.
37
Sun X, Ou Z, Xie M, et al. HSPB1 as a novel regulator of ferroptotic cancer cell death[J]. Oncogene, 2015, 34(45): 5617-5625.
38
Sun X, Ou Z, Chen R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells[J]. Hepatology, 2016, 63(1): 173-184.
39
Friedmann Angeli JP, Schneider M, Proneth B, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice[J]. Nat Cell Biol, 2014, 16(12): 1180-1191.
40
Yang WS, Kim KJ, Gaschler MM, et al. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis[J]. Proc Natl Acad Sci U S A, 2016, 113(34): E4966-E4975.
41
Conrad M, Friedmann Angeli JP. Glutathione peroxidase 4 (Gpx4) and ferroptosis: what's so special about it? [J]. 43 Mol Cell Oncol, 2015, 2(3): e995047.
42
Yuan H, Li X, Zhang X, et al. Identification of ACSL4 as a biomarker and contributor of ferroptosis[J]. Biochem Biophys Res Commun, 2016, 478(3): 1338-1343.
43
Hou W, Xie Y, Song X, et al. Autophagy promotes ferroptosis by degradation of ferritin[J]. Autophagy, 2016, 12(8): 1425-1428.
44
Bellelli R, Federico G, Matte' A, et al. NCOA4 Deficiency Impairs Systemic Iron Homeostasis[J]. Cell Rep, 2016, 14(3): 411-421.
45
Dixon SJ, Stockwell BR. The role of iron and reactive oxygen species in cell death[J]. Nat Chem Biol, 2014, 10(1): 9-17.
46
Gao M, Monian P, Pan Q, et al. Ferroptosis is an autophagic cell death process[J]. Cell Res, 2016, 26(9): 1021-1032.
47
Ou Y, Wang SJ, Li D, et al. Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses[J]. Proc Natl Acad Sci U S A, 2016, 13(44): E6806-E6812.
48
Skouta R, Dixon SJ, Wang J, et al. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models[J]. J Am Chem Soc, 2014, 136(12): 4551-4556.
49
Garg JP, Vucic D. Targeting Cell Death Pathways for Therapeutic Intervention in Kidney Diseases[J]. Semin Nephrol, 2016, 36(3): 153-161.
50
Matsushita M, Freigang S, Schneider C, et al. T cell lipid peroxidation induces ferroptosis and prevents immunity to infection[J]. J Exp Med, 2015, 212(4): 555-568.
51
Skouta R, Dixon SJ, Wang J, et al. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models[J]. J Am Chem Soc, 2014, 136(12): 4551-4556.
52
Linkermann A, Skouta R, Himmerkus N, et al. Synchronized renal tubular cell death involves ferroptosis[J]. Proc Natl Acad Sci U S A, 2014, 111(47): 16836-16841.
53
Yang WS, Stockwell BR. Ferroptosis: Death by Lipid Peroxidation[J]. Trends Cell Biol, 2016 26(3): 165-176.
54
Paller MS. Hemoglobin- and myoglobin-induced acute renal failure in rats: role of iron in nephrotoxicity[J]. Am J Physiol, 1988, 255(3 Pt 2): F539-F544.
55
Reeder BJ, Wilson MT. Desferrioxamine inhibits production of cytotoxic heme to protein cross-linked myoglobin: a mechanism to protect against oxidative stress without iron chelation[J]. Chem Res Toxicol, 2005, 18(6): 1004-1011.
56
Groebler LK, Liu J, Shanu A, et al. Comparing the potential renal protective activity of desferrioxamine B and the novel chelator desferrioxamine B-N-(3-hydroxyadamant-1-yl) carboxamide in a cell model of myoglobinuria[J]. Biochem J, 2011, 435(3): 669-677.
57
Kontoghiorghes GJ, Pattichi K, Hadjigavriel M, et al. Transfusional iron overload and chelation therapy with deferoxamine and deferiprone (L1)[J]. Transfus Sci, 2000, 23(3): 211-223.
58
Dixon SJ, Patel DN, Welsch M, et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis[J]. Elife, 2014, 3: e02523.
59
Wang AW, Song L, Miao J, et al. Baicalein attenuates angiotensin II-induced cardiac remodeling via inhibition of AKT/mTOR, ERK1/2, NF-κB, and calcineurin signaling pathways in mice[J]. Am J Hypertens, 2015, 28(4): 518-526.
60
Chen HM, Liou SF, Hsu JH, et al. Baicalein inhibits HMGB1 release and MMP-2/-9 expression in lipopolysaccharide-induced cardiac hypertrophy[J]. Am J Chin Med, 2014, 42(4): 785-797.
61
Lai CC, Huang PH, Yang AH, et al. Baicalein, a Component of Scutellaria baicalensis, Attenuates Kidney Injury Induced by Myocardial Ischemiaand Reperfusion[J]. Planta Med, 2016, 82(3): 181-189.
62
Xie Y, Song X, Sun X, et al. Identification of baicalein as a ferroptosis inhibitor by natural product library screening[J]. Biochem Biophys Res Commun, 2016, 473(4): 775-780.
63
Albert C, Haase M, Bellomo R, et al. High cut-off and high-flux membrane haemodialysis in a patient with rhabdomyolysis-associated acute kidney injury[J]. Crit Care Resusc, 2012, 14(2): 159-162.
64
Heyne N, Guthoff M, Krieger J, et al. High cut-off renal replacement therapy for removal of myoglobin in severe rhabdomyolysis and acute kidney injury: a case series[J]. Nephron Clin Pract, 2012, 121(3-4): c159-c164.
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