Klotho基因多态性与高血压左室肥厚的关系
|
摘要
背景与目的
原发性高血压(essential hypertension,EH)是一种常见的以血压升高为主要临床表现的综合征,其病因包含遗传因素与环境因素两方面。一般认为遗传因素占40%,环境因素占60%。高血压严重影响人体重要脏器如心、脑、肾的结构和功能,是多种心血管疾病的重要危险因素和病因。长期压力负荷增高,可刺激心肌细胞肥大和间质纤维化,高血压主要引起左心室肥厚和扩张。近年来高血压的发病率不断上升,高血压心脏病的发病率也越来越高。
Klotho基因是日本学者Kuro-o等于1997年发现的与人类衰老表型密切相关的基因,由于Klotho基因hnRNA剪切的不同,Klotho基因在人和小鼠体内表达的蛋白质均分为膜型和分泌型两种,其在人体内主要表达分泌型蛋白,该蛋白被认为是一种具有激素样作用的蛋白。Klotho基因及其所表达的蛋白质与一些随着衰老而发生的疾病的关系逐渐成为研究热点。有研究表明Klotho基因多态性与血压调节有关,但Klotho基因多态性及Klotho蛋白与高血压左室肥厚的关系的研究国内外尚未见文献报道。本文研究并探讨了Klotho基因多态性、血清Klotho蛋白水平、血清NO水平和高血压左室肥厚的关系,从而为高血压及高血压左室肥厚的临床防治提供了一定的理论依据。
方法
选择原发性高血压患者158例,根据是否合并左室肥厚,分为高血压组(EH组)76例和高血压左室肥厚组(EH-LVH组)82例,同时入选69例体检正常者作为对照组(Control组)。通过等位基因特异性引物PCR (ASP-PCR)技术检测Klotho基因G395A位点和C370S位点多态性,酶联免疫吸附法测定血清Klotho蛋白浓度,血清一氧化氮浓度水平的测定采用硝基还原酶法。
结果
1.G395A位点多态性GG、GA和AA在三组的分布频率有显著差异(x2=16.976,P＜0.05),EH组和EH-LVH组A等位基因频率均高于Control组,差异有统计学意义(P＜0.05)。EH-LVH组各基因型分布频率与对照组相比差异有统计学意义(x2=14.307,P＜0.05),AA基因型频率高于对照组,差异有统计学意义(P＜0.05)。
2.C370S位点多态性CC、CS、SS在三组的分布频率有差异,该差异有统计学意义(x2=15.827,P＜0.05)。EH-LVH组SS基因型频率为高于Control组,差异有统计学意义(x2=14.985,P＜0.05)。EH组和EH-LVH组C等位基因频率均低于Control组,差异有统计学意义(P＜0.05)。
3.EH组、EH-LVH组和Control组血清Klotho蛋白水平分别为(10.57±2.31)、(9.61±2.45)、(12.08±2.35)pg/mL, EH组和EH-LVH组均较control组降低(P<0.05), EH-LVH组低于EH组(P＜0.05)。
4.3组GG基因型血清Klotho蛋白水平高于GA和AA基因型(P＜0.05)；3组CC基因型血清Klotho蛋白水平高于CS和SS基因型(P＜0.05)。
5.EH组、EH-LVH组和Control组的血清NO浓度分别为62.25±5.12umol/L,65.37±6.29umol/L,73.82±5.68umol/L。EH组及EH-LVH组均低于Control组(P＜0.05)。
结论
1. Klotho基因多态性可能与原发性高血压及左室肥厚的发生有关。G395A位点的AA基因型和C370S位点的SS基因型易患高血压,A等位基因和S等位基因可能是高血压的易感基因,G等位基因和C等位基因可能对EH及EH-LVH的发生具有保护作用,GG基因型和CC基因型可能对EH及EH-LVH的发生有保护作用。
2. Klotho基因多态性与血清Klotho蛋白水平相关。血清Klotho蛋白水平升高可能是EH及EH-LVH的保护性因素。
3.血清NO浓度可能与原发性高血压及左室肥厚的发生有关,NO浓度上升可能是EH及EH-LVH的保护性因素。
Background and Objective
Essential hypertension (EH) is a common syndrome,its etiology includes both genetic and environmental factors. Generally believed that genetic factors accounted for40%and that environmental factors accounted for60%. Hypertension is an important cause of a variety of cardiovascular and cerebrovascular disease. Hypertension seriously affect vital organs's structure and function, such as heart, brain and kidney. Long-term increased pressure load can stimulate myocardial cells hypertrophy and interstitial fibrosis. Hypertension is the main cause of left ventricular hypertrophy and expansion. In recent years, the incidence of hypertension is rising, hypertensive heart disease incidence is increasing too.
Klotho gene is a new gene related to human aging closely, it was found by Kuro-o in1997. Due to the hnRNA shear difference, the protein that klotho gene express in humans and mice were divided into membrane type and secreted. The protein expressed mainly in the human body is secreted protein, the protein is considered to have hormone-like effects. The gene has relationship with a number of diseases which occur with aging. Studies have shown that Klotho gene polymorphism is associated with blood pressure regulation. This study aims at investigating the relationship between the Klotho gene G-395A polymorphism, C370S polymorphism, serum Klotho protein level, and serum NO level in hypertension patients with left ventricular hypertrophy(LVH).
Methods
This study selected76Essential Hypertension patients,82EH with LVH patients and69contral. Allele-specific primer(ASP)PCR technique was used to detect genotype of the klotho gene G395A and C370S SNP.Enzyme-linked immunosorbent assay was used to measure serum Klotho protein level, and chemical colorimetric method was used tomeasure serum NO level.
Results
There was a significant difference in the three groups in the distribution frequency of Klotho gene G395A polymorphism(X2=16.976,P<0.05). The frequencies of A allele in the EH-LVH group and the EH group were significant different from the control group (P<0.05). And the distribution frequency of AA genetype in the EH-LVH group were higher than the control group(χ2=14.307, P<0.05).
There was a significant difference in the three groups in the distribution frequency of Klotho gene C370S polymorphism(X2=15.827,P<0.05). The distribution frequency of SS genetype in the EH-LVH group were higher than the control group(x2=14.985, P<0.05). The frequencies of C allele in the EH-LVH group and the EH group were lower than the control group. The difference was statistically significant (P<0.05).
The Klotho protein concentration in the EH patients with or without LVH was significantly lower than that of control (P<0.05).
The NO concentration in the EH patients with or without LVH was significantly lower than that of control (P<0.05).
In the three groups, the concentration of Klotho protein in GG genotype were higher than those in GA genotype and AA genotype (P<0.05),the concentration of Klotho protein in CC genotype were higher than those in CS genotype and SS genotype (P<0.05).
Conclusion
The Klotho gene G395A polymorphism is associated with EH and EH-LVH patients. The AA genetype is liable to hypertension.The A allele may be a susceptibility gene for hypertension. The GG genetype may be an protective factor for hypertension and LVH. The Klotho gene C370S polymorphism is associated with EH and EH-LVH patients. The AA genetype is liable to hypertension.The A allele may be a susceptibility gene for hypertension. The GG genetype may be an protective factor for hypertension and LVH. The increase of plasma Klotho protein level might be a protective factor of hypertension and left ventricular hypertrophy caused by hypertension
原发性高血压(essential hypertension,EH)是一种常见的以血压升高为主要临床表现的综合征,其病因包含遗传因素与环境因素两方面。一般认为遗传因素占40%,环境因素占60%。高血压严重影响人体重要脏器如心、脑、肾的结构和功能,是多种心血管疾病的重要危险因素和病因。长期压力负荷增高,可刺激心肌细胞肥大和间质纤维化,高血压主要引起左心室肥厚和扩张。近年来高血压的发病率不断上升,高血压心脏病的发病率也越来越高。
Klotho基因是日本学者Kuro-o等于1997年发现的与人类衰老表型密切相关的基因,由于Klotho基因hnRNA剪切的不同,Klotho基因在人和小鼠体内表达的蛋白质均分为膜型和分泌型两种,其在人体内主要表达分泌型蛋白,该蛋白被认为是一种具有激素样作用的蛋白。Klotho基因及其所表达的蛋白质与一些随着衰老而发生的疾病的关系逐渐成为研究热点。有研究表明Klotho基因多态性与血压调节有关,但Klotho基因多态性及Klotho蛋白与高血压左室肥厚的关系的研究国内外尚未见文献报道。本文研究并探讨了Klotho基因多态性、血清Klotho蛋白水平、血清NO水平和高血压左室肥厚的关系,从而为高血压及高血压左室肥厚的临床防治提供了一定的理论依据。
方法
选择原发性高血压患者158例,根据是否合并左室肥厚,分为高血压组(EH组)76例和高血压左室肥厚组(EH-LVH组)82例,同时入选69例体检正常者作为对照组(Control组)。通过等位基因特异性引物PCR (ASP-PCR)技术检测Klotho基因G395A位点和C370S位点多态性,酶联免疫吸附法测定血清Klotho蛋白浓度,血清一氧化氮浓度水平的测定采用硝基还原酶法。
结果
1.G395A位点多态性GG、GA和AA在三组的分布频率有显著差异(x2=16.976,P＜0.05),EH组和EH-LVH组A等位基因频率均高于Control组,差异有统计学意义(P＜0.05)。EH-LVH组各基因型分布频率与对照组相比差异有统计学意义(x2=14.307,P＜0.05),AA基因型频率高于对照组,差异有统计学意义(P＜0.05)。
2.C370S位点多态性CC、CS、SS在三组的分布频率有差异,该差异有统计学意义(x2=15.827,P＜0.05)。EH-LVH组SS基因型频率为高于Control组,差异有统计学意义(x2=14.985,P＜0.05)。EH组和EH-LVH组C等位基因频率均低于Control组,差异有统计学意义(P＜0.05)。
3.EH组、EH-LVH组和Control组血清Klotho蛋白水平分别为(10.57±2.31)、(9.61±2.45)、(12.08±2.35)pg/mL, EH组和EH-LVH组均较control组降低(P<0.05), EH-LVH组低于EH组(P＜0.05)。
4.3组GG基因型血清Klotho蛋白水平高于GA和AA基因型(P＜0.05)；3组CC基因型血清Klotho蛋白水平高于CS和SS基因型(P＜0.05)。
5.EH组、EH-LVH组和Control组的血清NO浓度分别为62.25±5.12umol/L,65.37±6.29umol/L,73.82±5.68umol/L。EH组及EH-LVH组均低于Control组(P＜0.05)。
结论
1. Klotho基因多态性可能与原发性高血压及左室肥厚的发生有关。G395A位点的AA基因型和C370S位点的SS基因型易患高血压,A等位基因和S等位基因可能是高血压的易感基因,G等位基因和C等位基因可能对EH及EH-LVH的发生具有保护作用,GG基因型和CC基因型可能对EH及EH-LVH的发生有保护作用。
2. Klotho基因多态性与血清Klotho蛋白水平相关。血清Klotho蛋白水平升高可能是EH及EH-LVH的保护性因素。
3.血清NO浓度可能与原发性高血压及左室肥厚的发生有关,NO浓度上升可能是EH及EH-LVH的保护性因素。
Background and Objective
Essential hypertension (EH) is a common syndrome,its etiology includes both genetic and environmental factors. Generally believed that genetic factors accounted for40%and that environmental factors accounted for60%. Hypertension is an important cause of a variety of cardiovascular and cerebrovascular disease. Hypertension seriously affect vital organs's structure and function, such as heart, brain and kidney. Long-term increased pressure load can stimulate myocardial cells hypertrophy and interstitial fibrosis. Hypertension is the main cause of left ventricular hypertrophy and expansion. In recent years, the incidence of hypertension is rising, hypertensive heart disease incidence is increasing too.
Klotho gene is a new gene related to human aging closely, it was found by Kuro-o in1997. Due to the hnRNA shear difference, the protein that klotho gene express in humans and mice were divided into membrane type and secreted. The protein expressed mainly in the human body is secreted protein, the protein is considered to have hormone-like effects. The gene has relationship with a number of diseases which occur with aging. Studies have shown that Klotho gene polymorphism is associated with blood pressure regulation. This study aims at investigating the relationship between the Klotho gene G-395A polymorphism, C370S polymorphism, serum Klotho protein level, and serum NO level in hypertension patients with left ventricular hypertrophy(LVH).
Methods
This study selected76Essential Hypertension patients,82EH with LVH patients and69contral. Allele-specific primer(ASP)PCR technique was used to detect genotype of the klotho gene G395A and C370S SNP.Enzyme-linked immunosorbent assay was used to measure serum Klotho protein level, and chemical colorimetric method was used tomeasure serum NO level.
Results
There was a significant difference in the three groups in the distribution frequency of Klotho gene G395A polymorphism(X2=16.976,P<0.05). The frequencies of A allele in the EH-LVH group and the EH group were significant different from the control group (P<0.05). And the distribution frequency of AA genetype in the EH-LVH group were higher than the control group(χ2=14.307, P<0.05).
There was a significant difference in the three groups in the distribution frequency of Klotho gene C370S polymorphism(X2=15.827,P<0.05). The distribution frequency of SS genetype in the EH-LVH group were higher than the control group(x2=14.985, P<0.05). The frequencies of C allele in the EH-LVH group and the EH group were lower than the control group. The difference was statistically significant (P<0.05).
The Klotho protein concentration in the EH patients with or without LVH was significantly lower than that of control (P<0.05).
The NO concentration in the EH patients with or without LVH was significantly lower than that of control (P<0.05).
In the three groups, the concentration of Klotho protein in GG genotype were higher than those in GA genotype and AA genotype (P<0.05),the concentration of Klotho protein in CC genotype were higher than those in CS genotype and SS genotype (P<0.05).
Conclusion
The Klotho gene G395A polymorphism is associated with EH and EH-LVH patients. The AA genetype is liable to hypertension.The A allele may be a susceptibility gene for hypertension. The GG genetype may be an protective factor for hypertension and LVH. The Klotho gene C370S polymorphism is associated with EH and EH-LVH patients. The AA genetype is liable to hypertension.The A allele may be a susceptibility gene for hypertension. The GG genetype may be an protective factor for hypertension and LVH. The increase of plasma Klotho protein level might be a protective factor of hypertension and left ventricular hypertrophy caused by hypertension
引文
[1]Tao S, Wu X, Duan X, et al. Hypertension prevalence and status of awareness, treatment and control in China [J]. Chinese medical journal,1995,108(7):483.
[2]王增武,王馨,李贤,et al.中年人群高血压患病率及控制状况的演变趋势[J].中华高血压杂志,2008,16(011)：1033-1036.
[3]刘力生.中国高血压防治指南2010[J].中华高血压杂志,2011,(08)：701-743.
[4]高玖鸣,王文.高血压及心脑血管疾病流行病学的最新数据：美国心脏病和卒中年报2008[J].中华高血压杂志,2009,(006)：494-495.
[5]Ruilope LM. The kidney as a sensor of cardiovascular risk in essential hypertension [J]. Journal of the American Society of Nephrology,2002,13(suppl 3):S165-S168.
[6]Matsumura Y, Aizawa H, Shiraki-Iida T, et al.Identification of the human klotho gene and its two transcripts encoding membrane and secreted Klotho protein[J].Biochem Biophys Res Commun,1998,242:626-630.
[7]Bloch L, Sineshchekova O, Reichenbach D, et al. Klotho is a substrate for alpha-, beta-and gamma-secretase. FEBS Lett,2009,583:3221-3224.
[8]Tatar M, Bartke A,Antebi A. The endocrine regulation of aging by insulin-like signals[J]. Science,2003;299(5611):1346-1351.
[9]Yamamoto M, Clark JD, Pastor JV,et al.Regulation of oxidative stress by the anti-aging hormone klotho[J].J Biol Chem,2005;280(45):38029-38034.
[10]Kops G, Dansen T,Polderman P.et al.Forkhead transcription factor FOXO3 aprotects quiescent cells from oxidative strees[J].Nature,2002;419(6904):316-321.
[11]Wang Y, Sun Z. Current understanding of klotho[J].Aging Res Rev,2009;8(1):43-51.
[12]Liu H, Fergusson MM, Castilho RM,et al.Augmented Wnt signaling in a mammalian model of accelerated aging[J].Science,2007;317(5839):803-806.
[13]Bailey-Downs L,Sun Z. RNAi Knockdown of Klotho Gene Causes Hypertension and Kidney Damage [J]. Circulation,2010,122(21 Supplement):A12293.
[14]Sahn DJ,DeMaria A, Kisslo J,et al. The Committee on M-mode standardization of the american Society of Echocardiography,"Recommendations regarding quantitation in M-Mode echocardiography:Results of a survey of echocardiographic measurements" Circulation,1978,58(6):1072-1083.
[15]Devereux RB, Reuchek N. Echocardiographic determination of left ventricular mass in man:Anatomic validation of the method. Circulation,1987,55:613.
[16]Casale PN.Value of echocardiographic assessment of left ventricular mass in predicting cardiovascular morbid events in hypertensive men. Am Inter Med,1986,105-173.
[17]Devereux RB,Alonso DR,Lutas EM,et al. Echocardiographic assessment of left ventricular hypertrophy:Comparison to necropsy findings. American Journal of cardiology,1986, 57,450-458.
[18]田家玮主编.心肌疾病超声诊断.北京：人民卫生出版社,2002,p25.
[19]杨昭庆,洪坤学,褚嘉佑.单核苷酸多态性的研究进展[J].国外医学遗传学分册,2002,23(1)：4-8.
[20]马厚勋,牛永红,李章勇,谢正祥.等位基因特异性引物PCR技术及其应用研究.生物技术,2005,15：15-18.
[21]Kuro M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotllo gene leads to a syndrome resembling ageing [J]. Nature,1997.390:45-51.
[22]Makoto Kuro-o. Klotho and aging[J]. Biochimica et Biophysica Acta(BBA)- General Subjects,2009,1790(10):1049-1058.
[23]Shimada T, Takeshita Y, Murohara T. Angiogenesis and vasculogenesis are impaired in the precocious-aging klotho mouse[J]. Circulation,2004,110 (9):1148-1155.
[24]尹扬光,黄岚,赵晓辉,等.非显微外科手术建立小鼠颈动脉损伤模型[J].中国应用生理学杂志,2008,24(1)：34—35.
[25]Yoshida T, Fujimori T, Nabeshima YI. Mediation of unusually high concentrations of 1, 25-dihydroxyvitamin D in homozygous klotho mutant mice by increased expression of renal 1α-hydroxylase gene [J]. Endocrinology,2002,143(2):683.
[26]Carroll N, Hughes L, McEntee G, et al. Investigation of the molecular response to folate metabolism inhibition [J]. J Nutr Biochem,2012.
[27]Huang CL. Regulation of ion channels by secreted klotho [J]. Adv Exp Med Biol,2012,728: 100-6.
[28]Kurosu H, Yamamoto M, Clark J D,et al. Suppression of aging in mice by the hormone Klotho. [J].Science,2005,309:1829-1833.
[29]Guerin AP,London GM,Marchais SJ.Arterial stiffening and vascular calcification in end-stage renal disease [J].Nephrol Dial Transp,2000,15;1014-1021.
[30]London GM, Guerin AP, Marchais SJ. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality[J].Nephrol Dial Transp,2003,18:1731-1740.
[31]Ohyama Y, Kurabayashi M, Masuda H,et al. Molecular cloning of rat klotho cDNA:markedly decreased expression of klotho by acute inflammatory stress[J]. Biochem Biophys Res Commun,1998,251(3):920-925.
[32]SaitoY, Nakamura T, Ohyama Y,et al. In vivo klotho gene delivery protects against endothelial dysfunction in multiple risk factor sundrome[J].Biochem Biophys Res Commun,2000,276(2)767-772.
[33]Sugiura H, Yoshida T, Mitobe M, etal. Klotho reduces apoptosis in experimental ischaemic acute kidney injury via HSP-70 [J]. Nephrol Dial Transplant,2010,25:60-68.
[34]薛永亮,唐宁,华晓东,等.一氧化氮与动脉粥样硬化.中国动脉硬化杂志,2009,17：698-701.
[35]晨阳,薛康,李春跃.原发性高血压与应激性高血压大鼠NO/NOS、ET的变化[J].中国医学物理学杂志,2006,23(1)：35-39.
[36]Cooke JP. Temporature-guided radiotrequency cather ablation with very large distal electrodes[J]. Circulation,1993,88(6):245-250.
[37]Perico N. Remuzzi G, Benigni A. Aging and the kidney [J]. Current Opinion in Nephrology and Hypertension,2011,20(3):312.
[38]Tian P, Wang H, Li L, et al. [Effect of klotho gene on the endothelial function of spontaneously hypertensive rats] [J]. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi,2011, 28(3):526-30.
[39]Ponomarenko JV, Merkulova TI, Orlova GV, et al. rSNP-guide, a database system for analysis of transcription factor binding to DNA with variations:application to genomeannotation. Nucleic Acids Res,2003,31:118-121.
[40]Rhee EJ,Oh KW, Lee WY,et al. The differential effects of age on the association of klotho gene polymorphisms with coronary artery disease[J]. Metabolism,2006,55:1344-1351.
[41]Levy D, Garrison RJ,Savage DD, et al. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. May 31 1990,322(22):1561-156.
[42]Vakili BA, Okin PM, Devereux RB. Prognostic implications of left ventricular hypertrophy. Am Heart J. Mar 2001,141(3):334-341.
[43]Di Tullio MR, Zwas DR, Sacco RL, et al. Left ventricular mass and geometry and the risk of ischemic stroke. Stroke. Oct 2003,34(10):2380-2384.
[44]Jissho S, Shimada K,Taguchi H,rt al.Impact of electrocardiographic left ventricular hypertrophy on the occurrence of cardiovascular events in elderly hypertensive patients-The Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients(JATOS)[J]. Circ J,2010,74(5):938-945
[45]Wachtell K, Okin PM, Olsen MH,et al. Regression of electrocardiographic left ventricular hypertrophy during antihypertensive therapy and reduction in sudden cardiac death:the LIFE Study[J].Circulation,2007,116(7):700-705.
[46]Ganau A, Devereux RB, Picketing TG,et al. Relation of left ventricular hemodynamic load and contractile performance to left ventticular mass in hypertension. Circulation. Jan 1990, 81(1):25-36.
[47]Galderisi M, Anderson KM, Wilson PW,et al. Echocardiographic evidence for the existence of a distinct diabetic cardiomyopathy(the Framingham Heart Study). Am J Cardiol. Jul 1 1991,68(1):85-89.
[48]Schmieder RE, Martus P, Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension. A meta-analysis of randomized double-blind studies. Jama. May 15 1996, 275(19):1507-1513.
[49]Shimizu I,Minamino T.Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents[J].J Clin Invesr,2012,120(5):1506-14
[50]Connell AW,Hypertension and insulin resistance [J].Hypertension,2009,54(3):462-464
[51]戴小良,刘小雨,王行宽,等.高血压左室肥厚与胰岛素抵抗的研究进展[J].医学综 述2006(12)：847-849.
[52]李永忠,徐义先,杨宝平.高血压左心室肥厚患者血清胰岛素生长因子Ⅰ、Ⅲ型前胶原浓度变化及其临床意义[J].临床荟萃,2010,25(16)：1384-1387.
[53]Mahmoudabady M, Mathieu M. Cardiac insulin-like growth factor-1 and cyclins gene expression in canine models of ischemic or overpacing cardiomyopathy[J].BMC Cardiovascular Disorders,2009,9:49.
[54]Takahashi Y,Kuro-O M,Ishikawa F.Aging mechanisms[J].Proc Natl Acad Sci USA, 2000,97(23):12407-08.
[55]徐瑞,张运,张梅,等.SHR心肌细胞内钙离子浓度改变与左室肥厚和功能的关系.中国病理生理杂志,2003,19(5)：642-644.
[56]Touyz RM, Fareh J, Thibault G,et al.Intracellular Ca2+ modulation by angiotensin II and endothelin-1 in cardiomyocytes and fibroblasts from hypertrophied hearts of spontaneously hypertensive rats[J].Hypertension,1996,28 (5)797-805.
[57]Sadoshima J, Izumo S. Molecular characterization of angiotensin Ⅱ-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype[J]. Circ Res,1993,73(3):413-423.
[58]Kurosu H,Ogawa Y, Miyoshi M,et al.Regulation of fibroblast growth factor-23 signaling by klotho[J].J Biol Chem,2006;281(10):6120-6123.
[59]Nabeshima Y. Toward a better understanding of Klotho[J]. Sci Aging Knowledge Environ,2006;2006(8):11.
[60]Nzietchueng R, El Shamieh S, Benachour H, et al. Klotho KL-VS genotype is involved in blood pressure regulation [J]. Clin Chim Acta,2011,412(19-20):1773-7.
[61]Medici D,Razzaque M,Deluca S,et al.FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis[J].J Cell Biol.2008; 182 (3):459-465.
[62]Kurz DJ, Decary S, Hong Y, et al. Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells[J]. J Cell Sci, 2004; 117(11):2417-2426.
[63]Wang Y. Sun Z. Klotho gene delivery prevents the progression of spontaneous hypertension and renal damage[J]. Hypertension,2009; 54(4):810-817.
[64]Rakugi H, Matsukawa N, Ishikawa K,et al. Anti-oxidative effect of Klotho on endothelial cells through Camp activation[J]. Endocrine,2007; 31(1):82-87.
[65]Xiao NM, Zhang YM, Zheng Q,et al.Klotho is a serum factor related to human aging[J]. Chin Med J,2004;117(5):742-747
[1]Wagner GR, Payne RM. Mitochondrial acetylation and diseases of aging. [J], J Aging Res,2011,234875.
[2]Manya H, Akasaka-Manya K, Endo T. Klotho protein deficiency and aging.[J], Geriatr Gerontol Int,2010,1:S80-7.
[3]Chateau MT, Araiz C, Descamps S,etal. Klotho interferes with a novel FGF-signalling pathway and insulin/Igf-like signalling to improve longevity and stress resistance in Caenorhabditis elegans. [J],Aging (AlbanyNY),2010,2(9):567-81.
[4]Kuro M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotllo gene leads to a syndrome resembling ageing [J]. Nature,1997.390:45-51.
[5]Matsumura Y, Aizawa H, Shiraki-Iida T, et al.Identification of the human klotho gene and its two transcripts encoding membrane and secreted Klotho protein[J].Biochem Biophys Res Commun,1998,242:626-630.
[6]Li SA, Watanabe M, Yamada H, et al.Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice[J]. Cell Struct Funct,2004;29(4):91-99.
[7]Balasubramanian P, Longo VD. Linking Klotho, Nrf2, MAP kinases and aging. [J], Aging (Albany NY),2010,2(10):632-3.
[8]Shih PH, Yen GC. Differential expressions of antioxidant status in aging rats:the role of transcriptional factor Nrf2 and MAPK signaling pathway.[J],Biogerontology,2007,8:71-80.
[9]Duce JA, Podvin S, Hollander W, etal.Gene rofile analysis implicates Klotho as an important contributor to aging changes in brain white matter of the rhesus monkey. [J],Glia,2008,56: 106-117.
[10]Ohyama Y, Kurabayashi M, Masuda H, etal.Molecular cloning of rat klotho cDNA: markedly decreased expression of klotho by acute inflammatory stress. [J],Biochem. Biophys. Res,1998,251:920-925.
[11]Shimizu H, Bolati D, Adijiang A, et al. Indoxyl Sulfate Downregulates Renal Expression of Klotho through Production of ROS and Activation of Nuclear Factor-κB. [J], Am J Nephrol, 2011,33(4):319-324.
[12]Rakugi H, Matsukawa N, Ishikawa K, etal. Anti-oxidative effect of Klotho on endothelial cells through cAMP activation.[J], Endocrine,2007,31(1):82-7.
[13]Tang R, Zhou Q, Liu Z, etal. Effects of fosinopril and losartan on renal Klotho expression and oxidative stress in spontaneously hypertensive rats. [J], Zhong Nan Da Xue Xue Bao Yi Xue Ban,2011,36(1):27-33.
[14]Yoon HE, Ghee JY, Piao S, etal. Angiotensin Ⅱ blockade upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy. [J], Nephrol Dial Transplant,2011,26(3):800-813.
[15]Tatar M, Bartke A,Antebi A. The endocrine regulation of aging by insulin-like signals[J].Science,2003;299(5611):1346-1351.
[16]Kuro-o, M. Klotho as a regulator of fibroblast growth factor signaling and phosphate/calcium metabolism. Curr Opin Nephrol Hypertens,2006; 15:437-441.
[17]Yu X, Ibrahimi OA, Goetz R, Zhang F, Davis SI, Garringer HJ, Linhardt RJ, Ornitz DM, MohammadiM&White KE. Analysis of the biochemical mechanisms for the endocrine actions of fibroblast growth factor-23. Endocrinology,2005; 146:4647-4656.
[18]Razzaque MS, Lanske B. Hypervitaminosis D and premature aging:lessons learned from FGF23 and Klotho mutant mice. Trends Mol Med,2006; 12(7):298-305.
[19]Razzaque MS, Sitara D, Taguchi T, St-Arnaud R, Lanske B. Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process. FASEB J,2006; 20(6):720-722.
[20]Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S&Yamashita T. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature,2006; 444:770-774.
[21]Yamamoto M, Clark JD, Pastor JV,et al.Regulation of oxidative stress by the anti-aging hormone klotho[J].J Biol Chem,2005;280(45):38029-38034.
[22]Kops G, Dansen T,Polderman P,et al.Forkhead transcription factor FOXO3 aprotects quiescent cells from oxidative strees[J].Nature,2002;419(6904):316-321.
[23]Wang Y, Sun Z. Current understanding of klotho[J].Aging Res Rev,2009;8(1):43-51.
[24]Liu H, Fergusson MM, Castilho RM,et al.Augmented Wnt signaling in a mammalian model of accelerated aging[J].Science,2007;317(5839):803-806.
[25]Wang Y, Kuro-o M, Sun Z. Klotho gene delivery suppresses Nox2 expression and attenuates oxidative stress in rat aortic smooth muscle cells via the cAMP-PKA pathway [J]. Aging Cell,2012.
[26]Maekawa Y, Ohishi M, Ikushima M, et al. Klotho protein diminishes endothelial apoptosis and senescence via a mitogen-activated kinase pathway [J]. Geriatrics & Gerontology International,2011.
[27]Guerin AP,London GM,Marchais SJ.Arterial stiffening and vascular calcification in end-stage renal disease [J].Nephrol Dial Transp,2000,15;1014-1021.
[28]London GM, Guerin AP, Marchais SJ. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality[J].Nephrol Dial Transp.2003,18:1731-1740.
[29]SaitoY, Nakamura T, Ohyama Y,et al. In vivo klotho gene delivery protects against endothelial dysfunction in multiple risk factor sundrome[J].Biochem Biophys Res Commun,2000,276(2)767-772.
[30]Sugiura H, Yoshida T, Mitobe M, etal. Klotho reduces apoptosis in experimental ischaemic acute kidney injury via HSP-70 [J]. Nephrol Dial Transplant,2010,25:60-68.
[31]晨阳,薛康,李春跃.原发性高血压与应激性高血压大鼠NO/NOS、ET的变化[J].中国医学物理学杂志,2006,23(1)：35-39.
[32]Cooke JP. Temporature-guided radiotrequency cather ablation with very large distal electrodes[J]. Circulation,1993,88(6):245-250.
[33]Majumdar V, Jose D, Christopher R. Influence of Klotho genotypes on plasma NOx levels in South Indian population [J]. Thrombosis research,2011.
[34]Perico N, Remuzzi G, Benigni A. Aging and the kidney [J]. Current Opinion in Nephrology and Hypertension,2011,20(3):312.
[35]Tian P, Wang H, Li L, et al. [Effect of klotho gene on the endothelial function of spontaneously hypertensive rats] [J]. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi,2011, 28(3):526-30.
[36]Ponomarenko JV, Merkulova TI, Orlova GV, et al. rSNP-guide, a database system for analysis of transcription factor binding to DNA with variations:application to genomeannotation. Nucleic Acids Res,2003,31:118-121.
[37]Rhee EJ,Oh KW, Lee WY.et al. The differential effects of age on the association of klotho gene polymorphisms with coronary artery disease[J]. Metabolism.2006,55:1344-1351.
[38]Nzietchueng R, El Shamieh S, Benachour H, et al. Klotho KL-VS genotype is involved in blood pressure regulation [J]. Clin Chim Acta,2011,412(19-20):1773-7.
[39]Van Kats JP, Schalekamp MA, Verdouw PD,et al.Intrarenal angiotensin Ⅱ:interstitial and cellular levels and site of production.Kidney Int,2001,60:2311-2317.
[40]Mitani H.Ishizaka N,Aizawa Y,et al.In Vivo klotho Gene Transfer Ameliorates Angiotensin Ⅱ-Induced Renal Damage.Hypertension,2002,39:838-843.
[41]Aizawa H, Saito Y, Nakamura T,et al.Downregulation of the klotho gene in the kidney under sustained circulatory stress in rats.Biochem Biophy Res Con,1998,249:865-871.
[42]Hu MC, Kuro OM, Moe OW. Secreted klotho and chronic kidney disease [J]. Adv Exp Med Biol,2012,728:126-57.
[43]Koh N,Fujimori T,Nishiguchi S,et al.Severely reduced production of klotho in human chronic renal failure kidney.Biochem Biophys Res Commun,2001,280:1015-1020.
[44]Young GH, Wu VC. KLOTHO methylation is linked to uremic toxins and chronic kidney disease [J]. Kidney Int,2012,81(7):611-2.
[45]Sugiura H, Yoshida T, Shiohira S, et al. Reduced Klotho Expression Level in Kidney Aggravates Renal Interstitial Fibrosis [J]. Am J Physiol Renal Physiol,2012.
[46]Devaraj S, Syed B, Chien A, et al. Validation of an immunoassay for soluble klotho protein: decreased levels in diabetes and increased levels in chronic kidney disease [J]. Am J Clin Pathol,2012,137(3):479-85.
[47]Terada Y, Shimamura Y, Hamada K, et al. Serum levels of soluble secreted [alpha]-Klotho are decreased in the early stages of chronic kidney disease, making it a probable novel biomarker for early diagnosis.2012.
[48]Akimoto T, Shiizaki K, Sugase T, et al. The relationship between the soluble Klotho protein and the residual renal function among peritoneal dialysis patients [J]. Clin Exp Nephrol, 2012.
[49]Margaglione M, Cappucci G, Colaizzo D, et al. The PAI-1 gene locus 4G/5G polymorphism is associated with a family history of coronary artery disease [J]. Arterioscler Thromb Vasc Biol,1998,18(2):152-6.
[50]Hoekstra T, Geleijnse JM, Kluft C, et al.4G/4G genotype of PAI-1 gene is associated with reduced risk of stroke in elderly [J]. Stroke,2003,34(12):2822-2828.
[51]Komatsu S, Panes J, Russell JM, et al. Effects of chronic arterial hypertension on constitutive and induced intercellular adhesion molecule-1 expression in vivo [J]. Hypertension,1997, 29(2):683-689.
[52]Cheek JD. Wirrig EE, Alfieri CM, et al. Differential activation of valvulogenic, chondrogenic, and osteogenic pathways in mouse models of myxomatous and calcific aortic valve disease [J]. J Mol Cell Cardiol,2012,52(3):689-700.
[53]Tangri N, Alam A, Wooten EC, et al. Lack of association of Klotho gene variants with valvular and vascular calcification in Caucasians:a candidate gene study of the Framingham Offspring Cohort [J]. Nephrology Dialysis Transplantation,2011,26(12):3998-4002.
[54]Takeshita K, Fujimori T, Kurotaki Y, et al. Sinoatrial node dysfunction and early unexpected death of mice with a defect of klotho gene expression [J]. Circulation,2004,109(14): 1776-1782.
[55]Gupta D, Brietzke S, Hayden MR, et al. Phosphate Metabolism in Cardiorenal Metabolic Disease [J]. Cardiorenal Med,2011,1(4):261-270.
[56]Kendrick J, Chonchol M. The role of phosphorus in the development and progression of vascular calcification [J]. Am J Kidney Dis,2011,58(5):826-34.
[57]Arking DE,Krebsova A,Macek M Sr, et al.Association of human aging with a functional variant of klotho [J].Proc Natl Acad Sci USA,2002;99:856-61.
[58]Arking DE,Atzmon G,Arking A,et al.Association between a functional variant of klotho gene and high-density lipoprotein cholesterol,blood pressure,stroke and longevity[J].Cirs Res,2005;96(4):412-58.
[59]Arking DE,Becker DM,Yanek LR,et al.Klotho allele status and the risk of early-on set occult coronary artery disease[J].Am J Hun Genet,2003;72(5):1154-61.
[60]Imamura A,Okumura K,Ogawa Y,et al.Klotho gene poly,orphism may be a genetic risk factor a therosclerotic coronary artery disease but not for vasospastic angina in Japanese[J].Clin Chin Acta,2006;371(1-2):66-70.
[61]Shimoyama Y, Nishio K,Hamajima N,et al.KLOTHO gene polymorphisms G-395A and C1818T are associated with lipid and glucose metabolism,bone mineral density and systolic blood pressure in Japanese healthy subjects[J].Clin Chim Acta,2009;406(1-2):134-8.
[2]王增武,王馨,李贤,et al.中年人群高血压患病率及控制状况的演变趋势[J].中华高血压杂志,2008,16(011)：1033-1036.
[3]刘力生.中国高血压防治指南2010[J].中华高血压杂志,2011,(08)：701-743.
[4]高玖鸣,王文.高血压及心脑血管疾病流行病学的最新数据：美国心脏病和卒中年报2008[J].中华高血压杂志,2009,(006)：494-495.
[5]Ruilope LM. The kidney as a sensor of cardiovascular risk in essential hypertension [J]. Journal of the American Society of Nephrology,2002,13(suppl 3):S165-S168.
[6]Matsumura Y, Aizawa H, Shiraki-Iida T, et al.Identification of the human klotho gene and its two transcripts encoding membrane and secreted Klotho protein[J].Biochem Biophys Res Commun,1998,242:626-630.
[7]Bloch L, Sineshchekova O, Reichenbach D, et al. Klotho is a substrate for alpha-, beta-and gamma-secretase. FEBS Lett,2009,583:3221-3224.
[8]Tatar M, Bartke A,Antebi A. The endocrine regulation of aging by insulin-like signals[J]. Science,2003;299(5611):1346-1351.
[9]Yamamoto M, Clark JD, Pastor JV,et al.Regulation of oxidative stress by the anti-aging hormone klotho[J].J Biol Chem,2005;280(45):38029-38034.
[10]Kops G, Dansen T,Polderman P.et al.Forkhead transcription factor FOXO3 aprotects quiescent cells from oxidative strees[J].Nature,2002;419(6904):316-321.
[11]Wang Y, Sun Z. Current understanding of klotho[J].Aging Res Rev,2009;8(1):43-51.
[12]Liu H, Fergusson MM, Castilho RM,et al.Augmented Wnt signaling in a mammalian model of accelerated aging[J].Science,2007;317(5839):803-806.
[13]Bailey-Downs L,Sun Z. RNAi Knockdown of Klotho Gene Causes Hypertension and Kidney Damage [J]. Circulation,2010,122(21 Supplement):A12293.
[14]Sahn DJ,DeMaria A, Kisslo J,et al. The Committee on M-mode standardization of the american Society of Echocardiography,"Recommendations regarding quantitation in M-Mode echocardiography:Results of a survey of echocardiographic measurements" Circulation,1978,58(6):1072-1083.
[15]Devereux RB, Reuchek N. Echocardiographic determination of left ventricular mass in man:Anatomic validation of the method. Circulation,1987,55:613.
[16]Casale PN.Value of echocardiographic assessment of left ventricular mass in predicting cardiovascular morbid events in hypertensive men. Am Inter Med,1986,105-173.
[17]Devereux RB,Alonso DR,Lutas EM,et al. Echocardiographic assessment of left ventricular hypertrophy:Comparison to necropsy findings. American Journal of cardiology,1986, 57,450-458.
[18]田家玮主编.心肌疾病超声诊断.北京：人民卫生出版社,2002,p25.
[19]杨昭庆,洪坤学,褚嘉佑.单核苷酸多态性的研究进展[J].国外医学遗传学分册,2002,23(1)：4-8.
[20]马厚勋,牛永红,李章勇,谢正祥.等位基因特异性引物PCR技术及其应用研究.生物技术,2005,15：15-18.
[21]Kuro M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotllo gene leads to a syndrome resembling ageing [J]. Nature,1997.390:45-51.
[22]Makoto Kuro-o. Klotho and aging[J]. Biochimica et Biophysica Acta(BBA)- General Subjects,2009,1790(10):1049-1058.
[23]Shimada T, Takeshita Y, Murohara T. Angiogenesis and vasculogenesis are impaired in the precocious-aging klotho mouse[J]. Circulation,2004,110 (9):1148-1155.
[24]尹扬光,黄岚,赵晓辉,等.非显微外科手术建立小鼠颈动脉损伤模型[J].中国应用生理学杂志,2008,24(1)：34—35.
[25]Yoshida T, Fujimori T, Nabeshima YI. Mediation of unusually high concentrations of 1, 25-dihydroxyvitamin D in homozygous klotho mutant mice by increased expression of renal 1α-hydroxylase gene [J]. Endocrinology,2002,143(2):683.
[26]Carroll N, Hughes L, McEntee G, et al. Investigation of the molecular response to folate metabolism inhibition [J]. J Nutr Biochem,2012.
[27]Huang CL. Regulation of ion channels by secreted klotho [J]. Adv Exp Med Biol,2012,728: 100-6.
[28]Kurosu H, Yamamoto M, Clark J D,et al. Suppression of aging in mice by the hormone Klotho. [J].Science,2005,309:1829-1833.
[29]Guerin AP,London GM,Marchais SJ.Arterial stiffening and vascular calcification in end-stage renal disease [J].Nephrol Dial Transp,2000,15;1014-1021.
[30]London GM, Guerin AP, Marchais SJ. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality[J].Nephrol Dial Transp,2003,18:1731-1740.
[31]Ohyama Y, Kurabayashi M, Masuda H,et al. Molecular cloning of rat klotho cDNA:markedly decreased expression of klotho by acute inflammatory stress[J]. Biochem Biophys Res Commun,1998,251(3):920-925.
[32]SaitoY, Nakamura T, Ohyama Y,et al. In vivo klotho gene delivery protects against endothelial dysfunction in multiple risk factor sundrome[J].Biochem Biophys Res Commun,2000,276(2)767-772.
[33]Sugiura H, Yoshida T, Mitobe M, etal. Klotho reduces apoptosis in experimental ischaemic acute kidney injury via HSP-70 [J]. Nephrol Dial Transplant,2010,25:60-68.
[34]薛永亮,唐宁,华晓东,等.一氧化氮与动脉粥样硬化.中国动脉硬化杂志,2009,17：698-701.
[35]晨阳,薛康,李春跃.原发性高血压与应激性高血压大鼠NO/NOS、ET的变化[J].中国医学物理学杂志,2006,23(1)：35-39.
[36]Cooke JP. Temporature-guided radiotrequency cather ablation with very large distal electrodes[J]. Circulation,1993,88(6):245-250.
[37]Perico N. Remuzzi G, Benigni A. Aging and the kidney [J]. Current Opinion in Nephrology and Hypertension,2011,20(3):312.
[38]Tian P, Wang H, Li L, et al. [Effect of klotho gene on the endothelial function of spontaneously hypertensive rats] [J]. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi,2011, 28(3):526-30.
[39]Ponomarenko JV, Merkulova TI, Orlova GV, et al. rSNP-guide, a database system for analysis of transcription factor binding to DNA with variations:application to genomeannotation. Nucleic Acids Res,2003,31:118-121.
[40]Rhee EJ,Oh KW, Lee WY,et al. The differential effects of age on the association of klotho gene polymorphisms with coronary artery disease[J]. Metabolism,2006,55:1344-1351.
[41]Levy D, Garrison RJ,Savage DD, et al. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. May 31 1990,322(22):1561-156.
[42]Vakili BA, Okin PM, Devereux RB. Prognostic implications of left ventricular hypertrophy. Am Heart J. Mar 2001,141(3):334-341.
[43]Di Tullio MR, Zwas DR, Sacco RL, et al. Left ventricular mass and geometry and the risk of ischemic stroke. Stroke. Oct 2003,34(10):2380-2384.
[44]Jissho S, Shimada K,Taguchi H,rt al.Impact of electrocardiographic left ventricular hypertrophy on the occurrence of cardiovascular events in elderly hypertensive patients-The Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients(JATOS)[J]. Circ J,2010,74(5):938-945
[45]Wachtell K, Okin PM, Olsen MH,et al. Regression of electrocardiographic left ventricular hypertrophy during antihypertensive therapy and reduction in sudden cardiac death:the LIFE Study[J].Circulation,2007,116(7):700-705.
[46]Ganau A, Devereux RB, Picketing TG,et al. Relation of left ventricular hemodynamic load and contractile performance to left ventticular mass in hypertension. Circulation. Jan 1990, 81(1):25-36.
[47]Galderisi M, Anderson KM, Wilson PW,et al. Echocardiographic evidence for the existence of a distinct diabetic cardiomyopathy(the Framingham Heart Study). Am J Cardiol. Jul 1 1991,68(1):85-89.
[48]Schmieder RE, Martus P, Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension. A meta-analysis of randomized double-blind studies. Jama. May 15 1996, 275(19):1507-1513.
[49]Shimizu I,Minamino T.Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents[J].J Clin Invesr,2012,120(5):1506-14
[50]Connell AW,Hypertension and insulin resistance [J].Hypertension,2009,54(3):462-464
[51]戴小良,刘小雨,王行宽,等.高血压左室肥厚与胰岛素抵抗的研究进展[J].医学综 述2006(12)：847-849.
[52]李永忠,徐义先,杨宝平.高血压左心室肥厚患者血清胰岛素生长因子Ⅰ、Ⅲ型前胶原浓度变化及其临床意义[J].临床荟萃,2010,25(16)：1384-1387.
[53]Mahmoudabady M, Mathieu M. Cardiac insulin-like growth factor-1 and cyclins gene expression in canine models of ischemic or overpacing cardiomyopathy[J].BMC Cardiovascular Disorders,2009,9:49.
[54]Takahashi Y,Kuro-O M,Ishikawa F.Aging mechanisms[J].Proc Natl Acad Sci USA, 2000,97(23):12407-08.
[55]徐瑞,张运,张梅,等.SHR心肌细胞内钙离子浓度改变与左室肥厚和功能的关系.中国病理生理杂志,2003,19(5)：642-644.
[56]Touyz RM, Fareh J, Thibault G,et al.Intracellular Ca2+ modulation by angiotensin II and endothelin-1 in cardiomyocytes and fibroblasts from hypertrophied hearts of spontaneously hypertensive rats[J].Hypertension,1996,28 (5)797-805.
[57]Sadoshima J, Izumo S. Molecular characterization of angiotensin Ⅱ-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype[J]. Circ Res,1993,73(3):413-423.
[58]Kurosu H,Ogawa Y, Miyoshi M,et al.Regulation of fibroblast growth factor-23 signaling by klotho[J].J Biol Chem,2006;281(10):6120-6123.
[59]Nabeshima Y. Toward a better understanding of Klotho[J]. Sci Aging Knowledge Environ,2006;2006(8):11.
[60]Nzietchueng R, El Shamieh S, Benachour H, et al. Klotho KL-VS genotype is involved in blood pressure regulation [J]. Clin Chim Acta,2011,412(19-20):1773-7.
[61]Medici D,Razzaque M,Deluca S,et al.FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis[J].J Cell Biol.2008; 182 (3):459-465.
[62]Kurz DJ, Decary S, Hong Y, et al. Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells[J]. J Cell Sci, 2004; 117(11):2417-2426.
[63]Wang Y. Sun Z. Klotho gene delivery prevents the progression of spontaneous hypertension and renal damage[J]. Hypertension,2009; 54(4):810-817.
[64]Rakugi H, Matsukawa N, Ishikawa K,et al. Anti-oxidative effect of Klotho on endothelial cells through Camp activation[J]. Endocrine,2007; 31(1):82-87.
[65]Xiao NM, Zhang YM, Zheng Q,et al.Klotho is a serum factor related to human aging[J]. Chin Med J,2004;117(5):742-747
[1]Wagner GR, Payne RM. Mitochondrial acetylation and diseases of aging. [J], J Aging Res,2011,234875.
[2]Manya H, Akasaka-Manya K, Endo T. Klotho protein deficiency and aging.[J], Geriatr Gerontol Int,2010,1:S80-7.
[3]Chateau MT, Araiz C, Descamps S,etal. Klotho interferes with a novel FGF-signalling pathway and insulin/Igf-like signalling to improve longevity and stress resistance in Caenorhabditis elegans. [J],Aging (AlbanyNY),2010,2(9):567-81.
[4]Kuro M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotllo gene leads to a syndrome resembling ageing [J]. Nature,1997.390:45-51.
[5]Matsumura Y, Aizawa H, Shiraki-Iida T, et al.Identification of the human klotho gene and its two transcripts encoding membrane and secreted Klotho protein[J].Biochem Biophys Res Commun,1998,242:626-630.
[6]Li SA, Watanabe M, Yamada H, et al.Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice[J]. Cell Struct Funct,2004;29(4):91-99.
[7]Balasubramanian P, Longo VD. Linking Klotho, Nrf2, MAP kinases and aging. [J], Aging (Albany NY),2010,2(10):632-3.
[8]Shih PH, Yen GC. Differential expressions of antioxidant status in aging rats:the role of transcriptional factor Nrf2 and MAPK signaling pathway.[J],Biogerontology,2007,8:71-80.
[9]Duce JA, Podvin S, Hollander W, etal.Gene rofile analysis implicates Klotho as an important contributor to aging changes in brain white matter of the rhesus monkey. [J],Glia,2008,56: 106-117.
[10]Ohyama Y, Kurabayashi M, Masuda H, etal.Molecular cloning of rat klotho cDNA: markedly decreased expression of klotho by acute inflammatory stress. [J],Biochem. Biophys. Res,1998,251:920-925.
[11]Shimizu H, Bolati D, Adijiang A, et al. Indoxyl Sulfate Downregulates Renal Expression of Klotho through Production of ROS and Activation of Nuclear Factor-κB. [J], Am J Nephrol, 2011,33(4):319-324.
[12]Rakugi H, Matsukawa N, Ishikawa K, etal. Anti-oxidative effect of Klotho on endothelial cells through cAMP activation.[J], Endocrine,2007,31(1):82-7.
[13]Tang R, Zhou Q, Liu Z, etal. Effects of fosinopril and losartan on renal Klotho expression and oxidative stress in spontaneously hypertensive rats. [J], Zhong Nan Da Xue Xue Bao Yi Xue Ban,2011,36(1):27-33.
[14]Yoon HE, Ghee JY, Piao S, etal. Angiotensin Ⅱ blockade upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy. [J], Nephrol Dial Transplant,2011,26(3):800-813.
[15]Tatar M, Bartke A,Antebi A. The endocrine regulation of aging by insulin-like signals[J].Science,2003;299(5611):1346-1351.
[16]Kuro-o, M. Klotho as a regulator of fibroblast growth factor signaling and phosphate/calcium metabolism. Curr Opin Nephrol Hypertens,2006; 15:437-441.
[17]Yu X, Ibrahimi OA, Goetz R, Zhang F, Davis SI, Garringer HJ, Linhardt RJ, Ornitz DM, MohammadiM&White KE. Analysis of the biochemical mechanisms for the endocrine actions of fibroblast growth factor-23. Endocrinology,2005; 146:4647-4656.
[18]Razzaque MS, Lanske B. Hypervitaminosis D and premature aging:lessons learned from FGF23 and Klotho mutant mice. Trends Mol Med,2006; 12(7):298-305.
[19]Razzaque MS, Sitara D, Taguchi T, St-Arnaud R, Lanske B. Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process. FASEB J,2006; 20(6):720-722.
[20]Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S&Yamashita T. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature,2006; 444:770-774.
[21]Yamamoto M, Clark JD, Pastor JV,et al.Regulation of oxidative stress by the anti-aging hormone klotho[J].J Biol Chem,2005;280(45):38029-38034.
[22]Kops G, Dansen T,Polderman P,et al.Forkhead transcription factor FOXO3 aprotects quiescent cells from oxidative strees[J].Nature,2002;419(6904):316-321.
[23]Wang Y, Sun Z. Current understanding of klotho[J].Aging Res Rev,2009;8(1):43-51.
[24]Liu H, Fergusson MM, Castilho RM,et al.Augmented Wnt signaling in a mammalian model of accelerated aging[J].Science,2007;317(5839):803-806.
[25]Wang Y, Kuro-o M, Sun Z. Klotho gene delivery suppresses Nox2 expression and attenuates oxidative stress in rat aortic smooth muscle cells via the cAMP-PKA pathway [J]. Aging Cell,2012.
[26]Maekawa Y, Ohishi M, Ikushima M, et al. Klotho protein diminishes endothelial apoptosis and senescence via a mitogen-activated kinase pathway [J]. Geriatrics & Gerontology International,2011.
[27]Guerin AP,London GM,Marchais SJ.Arterial stiffening and vascular calcification in end-stage renal disease [J].Nephrol Dial Transp,2000,15;1014-1021.
[28]London GM, Guerin AP, Marchais SJ. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality[J].Nephrol Dial Transp.2003,18:1731-1740.
[29]SaitoY, Nakamura T, Ohyama Y,et al. In vivo klotho gene delivery protects against endothelial dysfunction in multiple risk factor sundrome[J].Biochem Biophys Res Commun,2000,276(2)767-772.
[30]Sugiura H, Yoshida T, Mitobe M, etal. Klotho reduces apoptosis in experimental ischaemic acute kidney injury via HSP-70 [J]. Nephrol Dial Transplant,2010,25:60-68.
[31]晨阳,薛康,李春跃.原发性高血压与应激性高血压大鼠NO/NOS、ET的变化[J].中国医学物理学杂志,2006,23(1)：35-39.
[32]Cooke JP. Temporature-guided radiotrequency cather ablation with very large distal electrodes[J]. Circulation,1993,88(6):245-250.
[33]Majumdar V, Jose D, Christopher R. Influence of Klotho genotypes on plasma NOx levels in South Indian population [J]. Thrombosis research,2011.
[34]Perico N, Remuzzi G, Benigni A. Aging and the kidney [J]. Current Opinion in Nephrology and Hypertension,2011,20(3):312.
[35]Tian P, Wang H, Li L, et al. [Effect of klotho gene on the endothelial function of spontaneously hypertensive rats] [J]. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi,2011, 28(3):526-30.
[36]Ponomarenko JV, Merkulova TI, Orlova GV, et al. rSNP-guide, a database system for analysis of transcription factor binding to DNA with variations:application to genomeannotation. Nucleic Acids Res,2003,31:118-121.
[37]Rhee EJ,Oh KW, Lee WY.et al. The differential effects of age on the association of klotho gene polymorphisms with coronary artery disease[J]. Metabolism.2006,55:1344-1351.
[38]Nzietchueng R, El Shamieh S, Benachour H, et al. Klotho KL-VS genotype is involved in blood pressure regulation [J]. Clin Chim Acta,2011,412(19-20):1773-7.
[39]Van Kats JP, Schalekamp MA, Verdouw PD,et al.Intrarenal angiotensin Ⅱ:interstitial and cellular levels and site of production.Kidney Int,2001,60:2311-2317.
[40]Mitani H.Ishizaka N,Aizawa Y,et al.In Vivo klotho Gene Transfer Ameliorates Angiotensin Ⅱ-Induced Renal Damage.Hypertension,2002,39:838-843.
[41]Aizawa H, Saito Y, Nakamura T,et al.Downregulation of the klotho gene in the kidney under sustained circulatory stress in rats.Biochem Biophy Res Con,1998,249:865-871.
[42]Hu MC, Kuro OM, Moe OW. Secreted klotho and chronic kidney disease [J]. Adv Exp Med Biol,2012,728:126-57.
[43]Koh N,Fujimori T,Nishiguchi S,et al.Severely reduced production of klotho in human chronic renal failure kidney.Biochem Biophys Res Commun,2001,280:1015-1020.
[44]Young GH, Wu VC. KLOTHO methylation is linked to uremic toxins and chronic kidney disease [J]. Kidney Int,2012,81(7):611-2.
[45]Sugiura H, Yoshida T, Shiohira S, et al. Reduced Klotho Expression Level in Kidney Aggravates Renal Interstitial Fibrosis [J]. Am J Physiol Renal Physiol,2012.
[46]Devaraj S, Syed B, Chien A, et al. Validation of an immunoassay for soluble klotho protein: decreased levels in diabetes and increased levels in chronic kidney disease [J]. Am J Clin Pathol,2012,137(3):479-85.
[47]Terada Y, Shimamura Y, Hamada K, et al. Serum levels of soluble secreted [alpha]-Klotho are decreased in the early stages of chronic kidney disease, making it a probable novel biomarker for early diagnosis.2012.
[48]Akimoto T, Shiizaki K, Sugase T, et al. The relationship between the soluble Klotho protein and the residual renal function among peritoneal dialysis patients [J]. Clin Exp Nephrol, 2012.
[49]Margaglione M, Cappucci G, Colaizzo D, et al. The PAI-1 gene locus 4G/5G polymorphism is associated with a family history of coronary artery disease [J]. Arterioscler Thromb Vasc Biol,1998,18(2):152-6.
[50]Hoekstra T, Geleijnse JM, Kluft C, et al.4G/4G genotype of PAI-1 gene is associated with reduced risk of stroke in elderly [J]. Stroke,2003,34(12):2822-2828.
[51]Komatsu S, Panes J, Russell JM, et al. Effects of chronic arterial hypertension on constitutive and induced intercellular adhesion molecule-1 expression in vivo [J]. Hypertension,1997, 29(2):683-689.
[52]Cheek JD. Wirrig EE, Alfieri CM, et al. Differential activation of valvulogenic, chondrogenic, and osteogenic pathways in mouse models of myxomatous and calcific aortic valve disease [J]. J Mol Cell Cardiol,2012,52(3):689-700.
[53]Tangri N, Alam A, Wooten EC, et al. Lack of association of Klotho gene variants with valvular and vascular calcification in Caucasians:a candidate gene study of the Framingham Offspring Cohort [J]. Nephrology Dialysis Transplantation,2011,26(12):3998-4002.
[54]Takeshita K, Fujimori T, Kurotaki Y, et al. Sinoatrial node dysfunction and early unexpected death of mice with a defect of klotho gene expression [J]. Circulation,2004,109(14): 1776-1782.
[55]Gupta D, Brietzke S, Hayden MR, et al. Phosphate Metabolism in Cardiorenal Metabolic Disease [J]. Cardiorenal Med,2011,1(4):261-270.
[56]Kendrick J, Chonchol M. The role of phosphorus in the development and progression of vascular calcification [J]. Am J Kidney Dis,2011,58(5):826-34.
[57]Arking DE,Krebsova A,Macek M Sr, et al.Association of human aging with a functional variant of klotho [J].Proc Natl Acad Sci USA,2002;99:856-61.
[58]Arking DE,Atzmon G,Arking A,et al.Association between a functional variant of klotho gene and high-density lipoprotein cholesterol,blood pressure,stroke and longevity[J].Cirs Res,2005;96(4):412-58.
[59]Arking DE,Becker DM,Yanek LR,et al.Klotho allele status and the risk of early-on set occult coronary artery disease[J].Am J Hun Genet,2003;72(5):1154-61.
[60]Imamura A,Okumura K,Ogawa Y,et al.Klotho gene poly,orphism may be a genetic risk factor a therosclerotic coronary artery disease but not for vasospastic angina in Japanese[J].Clin Chin Acta,2006;371(1-2):66-70.
[61]Shimoyama Y, Nishio K,Hamajima N,et al.KLOTHO gene polymorphisms G-395A and C1818T are associated with lipid and glucose metabolism,bone mineral density and systolic blood pressure in Japanese healthy subjects[J].Clin Chim Acta,2009;406(1-2):134-8.