Nox4在糖尿病及慢性并发症中的作用研究进展
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摘要
随着生活方式的改变和预期寿命的延长,世界范围内糖尿病及其慢性并发症的患病率逐年升高。糖尿病慢性并发症(糖尿病肾病、糖尿病大血管病变、糖尿病心肌病、糖尿病视网膜病变、糖尿病神经病变等)是糖尿病患者致死致残的主要原因。还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶4(Nox4)是催化氧生成活性氧类(ROS)的关键酶,Nox4的活性直接受组织氧分压的调控,由Nox4生成的ROS通过氧化应激在糖尿病及其慢性并发症的发病及进展过程中发挥重要作用。
With the change of lifestyle and the extension of life expectancy,the prevalence of diabetes and its chronic complications is increasing year by year worldwide. Chronic complications of diabetes( diabetic nephropathy,diabetic macroangiopathy,diabetic cardiomyopathy,diabetic retinopathy,diabetic neuropathy,etc.) are the main causes of death and disability in diabetic patients. Reduced nicotinamide adenine dinucleotide phosphatase oxidase 4( Nox4) is a key enzyme catalyzing the formation of reactive oxygen species( ROS) from oxygen. Nox4 activity is directly regulated by tissue oxygen partial pressure. ROS generated by Nox4 plays an important role in the pathogenesis and progression of diabetes and its chronic complications through oxidative stress.
With the change of lifestyle and the extension of life expectancy,the prevalence of diabetes and its chronic complications is increasing year by year worldwide. Chronic complications of diabetes( diabetic nephropathy,diabetic macroangiopathy,diabetic cardiomyopathy,diabetic retinopathy,diabetic neuropathy,etc.) are the main causes of death and disability in diabetic patients. Reduced nicotinamide adenine dinucleotide phosphatase oxidase 4( Nox4) is a key enzyme catalyzing the formation of reactive oxygen species( ROS) from oxygen. Nox4 activity is directly regulated by tissue oxygen partial pressure. ROS generated by Nox4 plays an important role in the pathogenesis and progression of diabetes and its chronic complications through oxidative stress.
引文
[1] Guo S, Chen X. The human Nox4:Gene, structure, physiological function and pathological significance[J]. J Drug Target,2015,23(10):888-896.
[2] Nisimoto Y, Diebold BA, Cosentino-Gomes D, et al. Nox4:A hydrogen peroxide-generating oxygen sensor[J]. Biochemistry,2014,53(31):5111-5120.
[3] Anilkumar N,San Jose G, Sawyer I,et al. A 28-kDa splice variant of NADPH oxidase-4 is nuclear-localized and involved in redox signaling in vascular cells[J]. Arterioscler Thromb Vase Biol,2013,33(4):e104412.
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[5] Lambeth JD. NOX enzymes and the biology of reactive oxygen[J].Nat Rev Immunol,2004,4:181-189.
[6] Martyn KD, Frederick LM, von Loehneysen K,et al. Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases[J]. Cell Signal,2006,18(1):69-82.
[7] Schroder K,Zhang M,Benkhoff S,et al. Nox4 is a protective reactive oxygen species generating vascular NADPH oxidase[J]. Circ Res,2012,110(9):12174225.
[8] Syed I,Kyathanahalli CN,Jayaram B,et al. Increased phagocytelike NADPH oxidase and ROS generation in type 2 diabetic ZDF rat and human islets:Role of Rac1-JNK1/2 signaling pathway in mitochondrial dysregulation in the diabetic islet[J]. Diabetes,2012,60(11):2843-2852.
[9] Anvari E, Wikstrom P,Walum E,et al. The novel NADPH oxidase4 inhibitor GLX351322 counteracts glucose intolerance in high-fat diet-treated C57BL/6 mice[J]. Free Radic Res,2015,49(11):13084318.
[10] Gao S,Park BM,Cha SA,et al. Oxidative stress increases the risk of pancreaticβcell damage in chronic renal hypertensive rats[J].Physiol Rep,2016,4(16):e12900.
[11] Wang X,Elksnis A, Wikstrom P,et al. The novel NADPH oxidase4 selective inhibitor GLX7013114 counteracts human islet cell death in vitro[J]. PLoS One,2018,13(9):e0204271.
[12] Wang M, Zhang W, Xu S,et al. TRB3 mediates advanced glycation end product-induced apoptosis of pancreaticβ-cells through the protein kinase Cβpathway[J]. Int J Mol Med, 2017,40(1):130-136.
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[31] Hu F,Xue M,Li YJ,et al. Early Growth Response 1(Egrl)Is a Transcriptional Activator of NOX4 in Oxidative Stress of Diabetic Kidney Disease[J]. Diabetes Res,2018,2018:3405695.
[32] Thallas-Bonke V, Jha JC,Gray SP,et al. Nox-4 deletion reduces oxidative stress and injury by PKC-alpha-associated mechanisms in diabetic nephropathy[J]. Physiol Rep,2014,2(11):e12192.
[33] Jha JC,Gray SP, Barit D,et al. Genetic targeting or pharmacologic inhibition of NADPH oxidase nox4 provides renoprotection in long-term diabetic nephropathy[J]. J Am Soc Nephrol, 2014,25(6):1237-1254.
[34]Jha JC, Thallas-Bonke V, Banal C, et al. Podocyte-specific Nox4deletion affords renoprotection in a mouse model of diabetic nephropathy[J]. Diabetologia,2016,59(2):379-389.
[35] Ilatovskaya DV, Blass G, Palygin OA, et al. NOX4/TRPC6Pathway in Podocyte Calcium Regulation and Renal Damage in Diabetic Kidney Disease[J]. J Am Soc Nephrol,2018,29(7):19174927.
[36] You YH, Quach T, Saito R, et al. Metabolomics Reveals a Key Role for Fumarate in Mediating the Effects of NADPH Oxidase 4in Diabetic Kidney Disease[J]. J Am Soc Nephrol,2016,27(2):466-481.
[37] Zhao XP, Chang SY, Liao MC, et al. Hedgehog Interacting Protein Promotes Fibrosisand Apoptosis in Glomerular Endothelial Cells in Murine Diabetes[J]. Sci Rep,2018,8(1):5958.
[38] Gorin Y, Cavaglieri RC, Khazim K, et al. Targeting NADPH oxidase with a novel dual Noxl/Nox4 inhibitor attenuates renal pathology in type 1 diabetes[J]. Am J Physiol Renal Physiol,2015,308(11):F1276 4 287.
[39] Gray SP, Jha JC, Kennedy K,et al. Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno-and atheroprotection even in established micro and macro vascular disease[J].Diabetologia,2017,60(5):927-937.
[40] Sedeek M,Gutsol A,Montezano AC,et al. Renoprotective effects of a novel Noxl/4 inhibitor in a mouse model of type 2 diabetes[J]. ClinSci(Lond),2013,124(3):191-202.
[41] Cha JJ, Min HS, Kim KT, et al. APX-115, a first-in-class panNADPH oxidase(Nox)inhibitor, protects db/db mice from renal injury[J]. Lab Invest,2017,97(4):419-431.
[42] Dorotea D, Kwon G, Lee JH,et al. A pan-NADPH Oxidase Inhibitor Ameliorates Kidney Injury in Type 1 Diabetic Rats[J]. Pharmacology, 2018,102(3/4):180489.
[43] De Blasio MJ, Ramalingam A,Cao AH, et al. The superoxide dismutase mimetic tempol blunts diabetes-induced upregulation of NADPH oxidase and endoplasmic reticulum stress in a rat model of diabetic nephropathy[J]. Eur J Pharmacol,2017,807:12-20.
[44] Lee HJ, Lee DY,Mariappan MM,et al. Hydrogen sulfide inhibits high glucose-induced NADPH oxidase 4 expression and matrix increase by recruiting inducible nitric oxide synthase in kidney proximal tubular epithelial cells[J]. J Biol Chem,2017,292(14):5665-5675.
[45] Gray SP,Di Marco E, Okabe J,et al. NADPH oxidase I plays a key role in diabetes mellitus-accelerated atherosclerosis[J].Circulation,2013,127(18):1888-1902.
[46] Di Marco E,Gray SP. NOX4-derived reactive oxygen species limit fibrosis and inhibit proliferation of vascular smooth muscle cells in diabetic atherosclerosis[J]. Free Radic Biol Med,2016,97:556-567.
[47] Tan C,Day R,Bao S,et al. Group VIA phospholipase A2 mediates enhanced macrophage migration in diabetes mellitus by increasing expression of nicotinamide adenine dinucleotide phosphate oxidase 4[J]. Arterioscler Thromb Vase Biol, 2014,34(4):768-778.
[48] Rozentsvit A, Vinokur K,Samuel S,et al. Ellagic Acid Reduceds High Glucose-Induced Vascular Oxidative Stress Through ERK1/2/NOX4 Signaling Pathway[J]. Cell Physiol Biochem,2017,44(3):1174-4187.
[49]吴杰萍,郭志新,齐伟,等.艾塞那肽通过下调p22phox、NOX4和TGF-β_1减轻1型糖尿病大鼠主动脉的氧化应激损伤[J].中国动脉硬化杂志,2013,21(8):711-715.
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[51] Maalouf RM,Eid AA,Corin YC,et al. Nox4-derived reactive oxygen species mediate cardiomyocyte injury in early type 1 diabetes[J].Am J Physiol Cell Physiol,2012,302(3):C597-604.
[52] Zheng D, Dong S,Li T,et al. Exogenous Hydrogen Sulfide Attenuates Cardiac Fibrosis Through Reactive Oxygen Species Signal Pathways in Experimental Diabetes Mellitus Models[J]. Cell Physiol Biochem,2015,36(3):917-929.
[53] Fan L,Xiao Q,Zhang L,et al. CAPE-pN02 attenuates diabetic Cardiomyopathy through the NOX4/NF-κB pathway in STZinduced diabetic mice[J]. Biomed Pharmacother,2018,108:1640-1650.
[54]楚洪波,李冬梅,石搏,等.大豆皂苷对糖尿病大鼠心肌组织中Nox4 mRNA及p22phox mRNA表达的影响及其对心肌的保护作用[J].吉林大学学报(医学版),2013,39(2):251-254.
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[2] Nisimoto Y, Diebold BA, Cosentino-Gomes D, et al. Nox4:A hydrogen peroxide-generating oxygen sensor[J]. Biochemistry,2014,53(31):5111-5120.
[3] Anilkumar N,San Jose G, Sawyer I,et al. A 28-kDa splice variant of NADPH oxidase-4 is nuclear-localized and involved in redox signaling in vascular cells[J]. Arterioscler Thromb Vase Biol,2013,33(4):e104412.
[4] Carrichon L,Picciocchi A,Debeurme F,et al. Characterization of superoxide overproduction by the D-Loop(Nox4)-Nox2 cytochrome b(558)in phagocytes-differential sensitivity to calcium and phosphorylation events[J]. Biochim Biophys Acta Biomembranes,2011,1808(1):78-90.
[5] Lambeth JD. NOX enzymes and the biology of reactive oxygen[J].Nat Rev Immunol,2004,4:181-189.
[6] Martyn KD, Frederick LM, von Loehneysen K,et al. Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases[J]. Cell Signal,2006,18(1):69-82.
[7] Schroder K,Zhang M,Benkhoff S,et al. Nox4 is a protective reactive oxygen species generating vascular NADPH oxidase[J]. Circ Res,2012,110(9):12174225.
[8] Syed I,Kyathanahalli CN,Jayaram B,et al. Increased phagocytelike NADPH oxidase and ROS generation in type 2 diabetic ZDF rat and human islets:Role of Rac1-JNK1/2 signaling pathway in mitochondrial dysregulation in the diabetic islet[J]. Diabetes,2012,60(11):2843-2852.
[9] Anvari E, Wikstrom P,Walum E,et al. The novel NADPH oxidase4 inhibitor GLX351322 counteracts glucose intolerance in high-fat diet-treated C57BL/6 mice[J]. Free Radic Res,2015,49(11):13084318.
[10] Gao S,Park BM,Cha SA,et al. Oxidative stress increases the risk of pancreaticβcell damage in chronic renal hypertensive rats[J].Physiol Rep,2016,4(16):e12900.
[11] Wang X,Elksnis A, Wikstrom P,et al. The novel NADPH oxidase4 selective inhibitor GLX7013114 counteracts human islet cell death in vitro[J]. PLoS One,2018,13(9):e0204271.
[12] Wang M, Zhang W, Xu S,et al. TRB3 mediates advanced glycation end product-induced apoptosis of pancreaticβ-cells through the protein kinase Cβpathway[J]. Int J Mol Med, 2017,40(1):130-136.
[13] Guichard C, Moreau R, Pessayre D, el al. NOX family NADPH oxidases in liver and in pancreatic islets:A role in the metabolic syndrome and diabetes[J]. Biochem Soc Trans,2008,36(Pt 5):920-929.
[14] Han CY, Umemoto T, Omer M, et al. NADPH oxidase-derived factor genes in cultured adipocytes[J]. J Biol Chem,2012,287:10379-10393.
[15] Den Hartigh LJ,Omer M, Goodspeed L,et al. Adipocyte-Specific Deficiency of NADPH Oxidase 4 Delays the Onset of Insulin Resistance and Attenuates Adipose Tissue Inflammation in Obesity[J].Arterioscler Thromb Vase Biol,2017,37(3):466-475.
[16] Bouabout G, Ayme-Dietrich E, Jacob H, et al. Nox4 genetic inhibition in experimental hypertension and metabolic syndrome[J]. Arch Cardiovasc Dis,2018,111(1):41-52.
[17]岳萍萍,陈可洋,孔德润,等.KKAy小鼠聚酶合delta作用蛋白2致缺乏导致血糖异常的研究[J].安徽医科大学学报,2018,53(10):1527-1531.
[18] Cremonini E,Oteiza PI.(-)-Epicatechin and its metabolites prevent palmitate-induced NADPH oxidase upregulation,oxidative stress and insulin resistance in HepG2 cells[J]. Arch Biochem Biophys,2018,646:55-63.
[19] Yan J, Wang C,Jin Y,et al. Catalpol ameliorates hepatic insulin resistance in type 2 diabetes through acting on AMPK/NOX4/PI3K/AKT pathway[J]. Pharmacol Res,2018,130:466-480.
[20] Li Q,Su J,Jin SJ,et al. Argirein alleviates vascular endothelial insulin resistance through suppressing the activation of Nox4-dependent O_2~·production in diabetic rats[J]. Free Radic Biol Med,2018,121:169-179.
[21] Gorin Y, Block K. Nox4 and diabetic nephropathy:With a friend like this, who needs enemies[J]. Free Radic Biol Med, 2013,61:130-142.
[22] Sward P,Rippe B. Acute and sustained actions of hyperglycaemia on endothelial and glomerular barrier permeability[J]. Acta Physiol(Oxf),2012,204(3):294-307.
[23]张伟开,张玲.糖尿病患肾病者SOD-Mn基因多态性与肾功能、氧化性损伤的相关性[J].海南医学院学报,2018,24(14):1311-1318.
[24] Rhee EP. NADPH Oxidase 4 at the Nexus of Diabetes, Reactive Oxygen Species, and Renal Metabolism[J]. J Am Soc Nephrol,2016,27(2):337-339.
[25] Xia L, Wang H, Munk S,et al. High glucose activates PKC-zeta and NADPH oxidase through autocrine TGF-betal signaling in mesangial cells[J]. Am J Physiol Renal Physiol,2008,295(6):F1705-1714.
[26] Eid A A, Ford BM, Block K,et al. AMP-activated protein kinase(AMPK)negatively regulates Nox4-dependent activation of p53and epithelial cell apoptosis in diabetes[J]. J Biol Chem,2010,285(48):37503-37512.
[27] Eid AA, Lee DY, Roman LJ, et al. Sestrin 2 and AMPK connect hyperglycemia to Nox4-dependent endothelial nitric oxide synthase uncoupling and matrix protein expression[J]. Mol Cell Biol,2013,33(17):3439-3460.
[28] Eid AA,Ford BM,Bhandary B,et al. Mammalian target of rapamycin regulates Nox4-mediated podocyte depletion in diabetic renal injury[J]. Diabetes,2013,62(8):2935-2947.
[29] Eid S, Boutary S,Braych K,et al. mTORC2 Signaling Regulates Nox4-Induced Podocyte Depletion in Diabetes[J]. Antioxid Redox Signal,2016,25(13):703-719.
[30] Wan RJ, Li YH. MicroRNA146a/NAPDH oxidase4 decreases reactive oxygen species generation and inflammation in a diabetic nephropathy model[J]. Mol Med Rep,2018,17(3):4759-4766.
[31] Hu F,Xue M,Li YJ,et al. Early Growth Response 1(Egrl)Is a Transcriptional Activator of NOX4 in Oxidative Stress of Diabetic Kidney Disease[J]. Diabetes Res,2018,2018:3405695.
[32] Thallas-Bonke V, Jha JC,Gray SP,et al. Nox-4 deletion reduces oxidative stress and injury by PKC-alpha-associated mechanisms in diabetic nephropathy[J]. Physiol Rep,2014,2(11):e12192.
[33] Jha JC,Gray SP, Barit D,et al. Genetic targeting or pharmacologic inhibition of NADPH oxidase nox4 provides renoprotection in long-term diabetic nephropathy[J]. J Am Soc Nephrol, 2014,25(6):1237-1254.
[34]Jha JC, Thallas-Bonke V, Banal C, et al. Podocyte-specific Nox4deletion affords renoprotection in a mouse model of diabetic nephropathy[J]. Diabetologia,2016,59(2):379-389.
[35] Ilatovskaya DV, Blass G, Palygin OA, et al. NOX4/TRPC6Pathway in Podocyte Calcium Regulation and Renal Damage in Diabetic Kidney Disease[J]. J Am Soc Nephrol,2018,29(7):19174927.
[36] You YH, Quach T, Saito R, et al. Metabolomics Reveals a Key Role for Fumarate in Mediating the Effects of NADPH Oxidase 4in Diabetic Kidney Disease[J]. J Am Soc Nephrol,2016,27(2):466-481.
[37] Zhao XP, Chang SY, Liao MC, et al. Hedgehog Interacting Protein Promotes Fibrosisand Apoptosis in Glomerular Endothelial Cells in Murine Diabetes[J]. Sci Rep,2018,8(1):5958.
[38] Gorin Y, Cavaglieri RC, Khazim K, et al. Targeting NADPH oxidase with a novel dual Noxl/Nox4 inhibitor attenuates renal pathology in type 1 diabetes[J]. Am J Physiol Renal Physiol,2015,308(11):F1276 4 287.
[39] Gray SP, Jha JC, Kennedy K,et al. Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno-and atheroprotection even in established micro and macro vascular disease[J].Diabetologia,2017,60(5):927-937.
[40] Sedeek M,Gutsol A,Montezano AC,et al. Renoprotective effects of a novel Noxl/4 inhibitor in a mouse model of type 2 diabetes[J]. ClinSci(Lond),2013,124(3):191-202.
[41] Cha JJ, Min HS, Kim KT, et al. APX-115, a first-in-class panNADPH oxidase(Nox)inhibitor, protects db/db mice from renal injury[J]. Lab Invest,2017,97(4):419-431.
[42] Dorotea D, Kwon G, Lee JH,et al. A pan-NADPH Oxidase Inhibitor Ameliorates Kidney Injury in Type 1 Diabetic Rats[J]. Pharmacology, 2018,102(3/4):180489.
[43] De Blasio MJ, Ramalingam A,Cao AH, et al. The superoxide dismutase mimetic tempol blunts diabetes-induced upregulation of NADPH oxidase and endoplasmic reticulum stress in a rat model of diabetic nephropathy[J]. Eur J Pharmacol,2017,807:12-20.
[44] Lee HJ, Lee DY,Mariappan MM,et al. Hydrogen sulfide inhibits high glucose-induced NADPH oxidase 4 expression and matrix increase by recruiting inducible nitric oxide synthase in kidney proximal tubular epithelial cells[J]. J Biol Chem,2017,292(14):5665-5675.
[45] Gray SP,Di Marco E, Okabe J,et al. NADPH oxidase I plays a key role in diabetes mellitus-accelerated atherosclerosis[J].Circulation,2013,127(18):1888-1902.
[46] Di Marco E,Gray SP. NOX4-derived reactive oxygen species limit fibrosis and inhibit proliferation of vascular smooth muscle cells in diabetic atherosclerosis[J]. Free Radic Biol Med,2016,97:556-567.
[47] Tan C,Day R,Bao S,et al. Group VIA phospholipase A2 mediates enhanced macrophage migration in diabetes mellitus by increasing expression of nicotinamide adenine dinucleotide phosphate oxidase 4[J]. Arterioscler Thromb Vase Biol, 2014,34(4):768-778.
[48] Rozentsvit A, Vinokur K,Samuel S,et al. Ellagic Acid Reduceds High Glucose-Induced Vascular Oxidative Stress Through ERK1/2/NOX4 Signaling Pathway[J]. Cell Physiol Biochem,2017,44(3):1174-4187.
[49]吴杰萍,郭志新,齐伟,等.艾塞那肽通过下调p22phox、NOX4和TGF-β_1减轻1型糖尿病大鼠主动脉的氧化应激损伤[J].中国动脉硬化杂志,2013,21(8):711-715.
[50] Koike S, Yano S, Tanaka S,et al. Advanced Glycation End-Products Induce Apoptosis of Vascular Smooth Muscle Cells:A Mechanism for Vascular Calcification[J]. Int J Mol Sci,2016,17(9):E1567.
[51] Maalouf RM,Eid AA,Corin YC,et al. Nox4-derived reactive oxygen species mediate cardiomyocyte injury in early type 1 diabetes[J].Am J Physiol Cell Physiol,2012,302(3):C597-604.
[52] Zheng D, Dong S,Li T,et al. Exogenous Hydrogen Sulfide Attenuates Cardiac Fibrosis Through Reactive Oxygen Species Signal Pathways in Experimental Diabetes Mellitus Models[J]. Cell Physiol Biochem,2015,36(3):917-929.
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