继发性甲状旁腺功能亢进症患者FGFR1与Klotho蛋白在不同增生类型甲状旁腺组织中的表达及其意义
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摘要
目的探讨成纤维细胞生长因子受体1(fibroblast growth factor receptor 1,FGFR1)与Klotho蛋白在慢性肾衰竭继发性甲状旁腺功能亢进症(secondary hyperparathyroidism,SHPT)患者甲状旁腺细胞不同增生类型中的表达水平及临床意义。方法选取在苏州九龙医院肾内科住院行甲状旁腺全切术的SHPT患者25例为治疗组,以同期内该院体检中心的健康志愿者10例作为对照组。采用酶联免疫吸附技术测定对照组及治疗组患者手术前后血清磷、血清全段甲状旁腺激素(intact parathyroid hormone,iPTH)、成纤维细胞生长因子-23(fibroblast growth factor-23,FGF-23)和Klotho指标。治疗组病例依据手术切除甲状旁腺大小形态,对甲状旁腺增生参差明显的患者进行亚组分析,分为无明显增生组、弥漫性增生组和结节性增生组3个亚组,采用光镜及电镜观察其组织改变,并采用实时定量荧光Real-time PCR法检测各组甲状旁腺组织中的FGFR1和KLotho mRNA的表达,采用Western blot法检测其FGFR1和Klotho水平。结果治疗组血清FGF-23及血磷水平明显高于对照组,血清Klotho水平明显低于对照组。切除甲状旁腺组织的总质量与iPTH呈正相关。术后48 h治疗组血清iPTH较术前明显下降,术后48 h治疗组血清FGF-23水平与术前相比无明显下降。亚组分析显示,无明显增生组的甲状旁腺组织中FGFR1和Klotho蛋白水平高于弥漫性增生组和结节性增生组;相对于弥漫性增生组,结节性增生组的甲状旁腺组织中FGFR1和Klotho蛋白水平更低;各亚组中FGFR1和Klotho mRNA表达差异无统计学意义。结论尿毒症患者增生的甲状旁腺组织中FGFR1和Klotho蛋白表达明显减少,可能在肾性继发性甲状旁腺功能亢进的发生、发展过程中起重要作用。
Objective To investigate the different expressions of fibroblast growth factor receptor 1(FGFR1)and Klotho protein in parathyroid cells with different hyperplasia from secondary hyperparathyroidism(SHPT) patients. Methods A total of 25 SHPT patients with parathyroidectomy were recruited as the SHPT group.At the same period,10 healthy volunteers from medical center in the same hospital were enrolled as the healthy control group.Serum phosphorus,intact parathyroid hormone(iPTH),FGF-23 and Klotho were assayed by ELISA.SHPT patients were subdivided into three subgroups:no obvious hyperplasia,diffusible hyperplasia and nodular hyperplasia according to the degrees of hyperplasia.Their pathology changes were observed by light microscope and electron microscopy.The mRNA expressions of FGFR1 and Klotho in parathyroid tissues were examined by Real-time PCR method and their protein expressions were detected by Western blot.Results Compared with the healthy control group,the level of serum phosphorus and FGF-23 in SHPT patients were increased significantly and serum Klotho protein reduced significantly.The total mass of removal parathyroid tissue and serum iPTH were positively correlated.Serum iPTH were declined obviously 48 hours later compared with preoperative level,but serum FGF-23 had no significant change.The expressions of FGFR1 and Klotho proteins in no obvious hyperplasia subgroup were higher than those in others.The expressions of FGFR1 and Klotho in nodular hyperplasia were much lower than those in diffusible hyperplasia.The expressions of FGFR1 and Klotho mRNA showed no difference in each subgroup. Conclusions The expressions of FGFR1 and Klotho protein were significantly decreased in hyperplasia parathyroid of SHPT patients,which may contribute to the different types of parathyroid cell hyperplasia in SHPT patients.
Objective To investigate the different expressions of fibroblast growth factor receptor 1(FGFR1)and Klotho protein in parathyroid cells with different hyperplasia from secondary hyperparathyroidism(SHPT) patients. Methods A total of 25 SHPT patients with parathyroidectomy were recruited as the SHPT group.At the same period,10 healthy volunteers from medical center in the same hospital were enrolled as the healthy control group.Serum phosphorus,intact parathyroid hormone(iPTH),FGF-23 and Klotho were assayed by ELISA.SHPT patients were subdivided into three subgroups:no obvious hyperplasia,diffusible hyperplasia and nodular hyperplasia according to the degrees of hyperplasia.Their pathology changes were observed by light microscope and electron microscopy.The mRNA expressions of FGFR1 and Klotho in parathyroid tissues were examined by Real-time PCR method and their protein expressions were detected by Western blot.Results Compared with the healthy control group,the level of serum phosphorus and FGF-23 in SHPT patients were increased significantly and serum Klotho protein reduced significantly.The total mass of removal parathyroid tissue and serum iPTH were positively correlated.Serum iPTH were declined obviously 48 hours later compared with preoperative level,but serum FGF-23 had no significant change.The expressions of FGFR1 and Klotho proteins in no obvious hyperplasia subgroup were higher than those in others.The expressions of FGFR1 and Klotho in nodular hyperplasia were much lower than those in diffusible hyperplasia.The expressions of FGFR1 and Klotho mRNA showed no difference in each subgroup. Conclusions The expressions of FGFR1 and Klotho protein were significantly decreased in hyperplasia parathyroid of SHPT patients,which may contribute to the different types of parathyroid cell hyperplasia in SHPT patients.
引文
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[8] FACCINI JM.The ultrastructure of parathyroid glands removedfrompatientswithprimaryhyperparathyriodism:a report of 40 cases,in-cluding for carcinoma[J].J Pathol,1970,102(4):189-199.
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[11]闫军放,郝丽,张凌,等.α-Klotho在肾性甲状旁腺功能亢患者甲状旁腺组织中表达研究[J].安徽医学,2016,37(4):389-392.
[12]张建荣,孙振学,邵素荣,等.成纤维细胞生长因子受体-1与Klotho蛋白在慢性肾衰竭继发性甲状旁腺功能亢进症甲状旁腺组织中的表达[J].武警医学,2013,24(12):1043-1046.
[13]张建荣,孙振学,孙长丽.Klotho蛋白在甲状旁腺细胞弥漫性增生与结节性增生中的不同表达探讨[J].中国血液净化,2013,12(12):686-689.
[14]程晨,王宁宁,查小明.不同外科术式治疗严重继发性甲状腺功能亢进的比较[J].中华肾脏病杂志,2015,31(4):314-320.
[15] ZHANG L,XING C,SHEN C,et al.Diagnostic accuracy study of intraoperative and perioperative serum intact PTH level for successful parathyroidectomy in 501 secondary hyperparathyroidism patients[J].Sci Rep,2016,1038(10):1-6.
[2] KURO-O M,MATSUMURA Y,AIZAWA H,et al.Mutation of the mouse klotho gene leads to a syndrome resembling ageing[J].Nature,1997,390(6655):45-51.
[3] URAKAWA I,YAMAZAKI Y,SHIMADA T,et al.Klotho converts canonical FGF receptor into a specific receptor for FGF23[J].Nature,2006,444(7120):770.
[4] REGINA G,ANDREW B,OMAR A,et al.Molecular insights in the klotho-dependent,endocrine mode of action of fibroblast growth factor 19 subfamily members[J].Mol Cell Biol,2007,27(9):3417-3428.
[5] LANSKE B,,RAZZAQUE MS.Molecular interactions of FGF23 and PTH in phosphate regulation[J].Kidney Int,2014,86(6):1072-1074.
[6] HLROSHL K,YASUSHL O,MASAYOSHL M,et al.Regulation of fibroblast growth factor-23 signaling by klotho[J].J Biol Chem,2006,281(10):6120-6123.
[7] HSIEH CC,KURO-O M,ROSENBLATT KP,et al.The ASK1-Signalosome regulates p38MAPK activity in response to levels of endogenous oxidative stress in the Klotho mouse models of aging[J].Aging(Albany NY),2010,2(9):597-611.
[8] FACCINI JM.The ultrastructure of parathyroid glands removedfrompatientswithprimaryhyperparathyriodism:a report of 40 cases,in-cluding for carcinoma[J].J Pathol,1970,102(4):189-199.
[9] SAVERIO C,ANDREA S.Ultrastructure of human parathyroid cells in health and disease[J].Microsc Res Tech,1995,32(2):164-179.
[10] CINTI S,COLUSSI G,MINOLA E,et al.Parathyroid glands in primary hyperparathyroidism:an ultrastructural study of 50 cases[J].Hum Pathol,1986,17(10):1036-1046.
[11]闫军放,郝丽,张凌,等.α-Klotho在肾性甲状旁腺功能亢患者甲状旁腺组织中表达研究[J].安徽医学,2016,37(4):389-392.
[12]张建荣,孙振学,邵素荣,等.成纤维细胞生长因子受体-1与Klotho蛋白在慢性肾衰竭继发性甲状旁腺功能亢进症甲状旁腺组织中的表达[J].武警医学,2013,24(12):1043-1046.
[13]张建荣,孙振学,孙长丽.Klotho蛋白在甲状旁腺细胞弥漫性增生与结节性增生中的不同表达探讨[J].中国血液净化,2013,12(12):686-689.
[14]程晨,王宁宁,查小明.不同外科术式治疗严重继发性甲状腺功能亢进的比较[J].中华肾脏病杂志,2015,31(4):314-320.
[15] ZHANG L,XING C,SHEN C,et al.Diagnostic accuracy study of intraoperative and perioperative serum intact PTH level for successful parathyroidectomy in 501 secondary hyperparathyroidism patients[J].Sci Rep,2016,1038(10):1-6.