慢性肾脏病患者及动物模型中成纤维细胞生长因子21的表达及意义

The Expression and Significance of FGF-21 among Patients and Animal Model with Chronic Kidney Disease

目的：观察慢性肾脏病（CKD）患者和CKD动物模型中成纤维细胞生长因子21（FGF21）的表达及其与肾功能等因素的相关性，以探讨FGF21在CKD进展中的意义。方法临床研究：选取2012年在温州医科大学附属第二医院就诊的CKD患者200例，根据估算肾小球滤过率（eGFR）将患者分为CKD1～2期组（76例）、 CKD3～4期组（56例）和CKD5期组（68例）；另选取本院同期体检健康者40例（对照组）。检测所有受检者一般资料及外周血空腹血糖、空腹胰岛素、血脂、清蛋白、肌酐、尿素氮、尿酸、脂联素和FGF21水平。实验研究：取清洁级雄性8周龄C57BL/6小鼠36只，将其随机分为正常对照组（ C组）、模型组（ M组）、低剂量FGF21干预组（ M＋L组）和高剂量FGF21干预组（ M＋H组），每组9只，观察小鼠给药期间的生存状况，4周后处死小鼠，检测小鼠血清肌酐、尿素氮、尿酸、清蛋白水平，观察肾组织病理改变，并采用免疫组化方法检测肾组织中FGF21的表达情况。结果临床研究结果：对照组、 CKD1～2期组、 CKD3～4期组、 CKD5期组血清FGF21水平〔（147.3±12.2）、（402.9±35.0）、（845.8±238.7）、（1447.9±146.5） ng/L〕依次增加（P＜0.05）。 CKD患者中，合并糖尿病者血清FGF21水平高于非糖尿病者〔（1253.0±170.1） ng/L与（714.0±82.1） ng/L， P＜0.05〕。通过对年龄、性别、 BMI、糖尿病校正后， Pearson相关分析显示血清FGF21水平与三酰甘油、血肌酐、尿素氮、脂联素呈正相关（ P＜0.05），与低密度脂蛋白、高密度脂蛋白、 eGFR呈负相关（ P＜0.05）。实验研究结果： M组小鼠血肌酐、尿素氮、血尿酸水平较C组升高；与M组比较， FGF21干预后小鼠血肌酐、尿素氮、血尿酸水平升高，且M＋H组上述3项肾功能指标较M＋L组恶化（ P＜0.05）。光镜下肾组织病理显示M＋H组小鼠肾脏损伤较M＋L组加重；免疫组化检测显示， M组小鼠肾组织中FGF21表达较C组升高； FGF21干预后，随着FGF21干预剂量的增加，肾组织中FGF21表达亦升高。结论随着CKD病情的进展，患者血清FGF21水平逐渐升高。随着FGF21干预剂量的升高， CKD小鼠肾脏损伤加重。

ObjectiveTostudytheexpressionoffibroblastgrowthfactor21（FGF21）inpatientsandanimalmodel with chronic kidney disease （CKD）, and the correlation between FGF21 and renal function, and to investigate the significance of FGF21 in the development of CKD .Methods The clinical study： a total of 200 patients with CKD in the Second Hospital Af-filiated to Wenzhou Medical University were selected , CKD patients were divided into three groups according to the eGFR： CKD1-2 group （76 cases）, CKD3-4 group （56 cases） and CKD5 group （68 cases）; Meanwhile, 40 healthy examinees in our hospital were selected as control group .General information , levels of peripheral blood fasting glucose , fasting insulin , blood lip-id, albumin, creatinine, uric acid, adiponectin and FGF21 of all examinees were detected.The experimental study： thirty six male C57BL/6 rats of clean grade at 8 weeks were randomly divided into four groups： control group （C group）, model group （M group）, low dose FGF21 group （M＋L group） and high dose FGF21 group （M＋H group）, 9 in each group, living status of rats was observed during the administration period .Rats were sacrificed 4 weeks after surgery, levels of albumin, creatinine, uric acid and adiponectin were detected , pathological changes of renal tissue were observed , the expression of FGF21 in kidney tissue was detected by the immunohistochemistry .Results The results of clinical study： plasma FGF21 level in control group ,＆amp;nbsp; ObjectiveTostudytheexpressionoffibroblastgrowthfactor21（FGF21）inpatientsandanimalmodel with chronic kidney disease （CKD）, and the correlation between FGF21 and renal function, and to investigate the significance of FGF21 in the development of CKD .Methods The clinical study： a total of 200 patients with CKD in the Second Hospital Af-filiated to Wenzhou Medical University were selected , CKD patients were divided into three groups according to the eGFR： CKD1-2 group （76 cases）, CKD3-4 group （56 cases） and CKD5 group （68 cases）; Meanwhile, 40 healthy examinees in our hospital were selected as control group .General information , levels of peripheral blood fasting glucose , fasting insulin , blood lip-id, albumin, creatinine, uric acid, adiponectin and FGF21 of all examinees were detected.The experimental study： thirty six male C57BL/6 rats of clean grade at 8 weeks were randomly divided into four groups： control group （C group）, model group （M group）, low dose FGF21 group （M＋L group） and high dose FGF21 group （M＋H group）, 9 in each group, living status of rats was observed during the administration period .Rats were sacrificed 4 weeks after surgery, levels of albumin, creatinine, uric acid and adiponectin were detected , pathological changes of renal tissue were observed , the expression of FGF21 in kidney tissue was detected by the immunohistochemistry .Results The results of clinical study： plasma FGF21 level in control group ,＆amp;nbsp;CKD1-2 group, CKD3-4 group and CKD5 group 〔 （147.3 ±12.2）, （402.9 ±35.0）, （845.8 ±238.7）, （1 447.9 ±146.5） ng/L〕 increased in an order （P〈0.05） .Serum FGF-21 level in CKD patients with diabetes mellitus （DM） was significantly higher than that in CKD patients without DM 〔 （1 253.0 ±170.1） ng/L and （714.0 ±82.1） ng/L, P〈0.05〕. After adjusting for age, gender, body mass index （BMI） and DM, results of Pearson correlation analysis indicated that serum FGF21 level was positively correlated with triacylglycerol , creatinine, urea nitrogen and adiponectin （P〈0.05）, and serum FGF21 level was negatively correlated with low density lipoprotein , high density lipoprotein and eGFR （ P〈0.05） .The results of experimental study：levels of serum creatinine , urea nitrogen and blood uric acid in rats of M group were significantly higher than those in rats of C group .Levels of serum creatinine , urea nitrogen and serum uric acid in rats of FGF 21 group were signifi-cantly higher than those in rats of M group , the above 3 renal function indexes in M ＋H group were significantly worse than those in M＋L group （ P〈0.05） .Renal pathology examination under light microscope showed that renal injury of rats in M ＋H group was worse than that in M＋L group.Immunohistochemical staining revealed that the expression level of FGF 21 in renal tissue of M group was higher than that in renal tissue of C group .The expression level of FGF21 in renal tissue increased with FGF21 interven-tion dose.Conclusion The serum FGF21 level of patients increases with the development of CKD .Renal injury of CKD rats gets worse with FGF21 intervention dose.