棕色脂肪源性神经调节蛋白4对糖尿病肾病小鼠炎症保护作用的研究
目的:探讨棕色脂肪源性神经调节蛋白4（NRG4）对糖尿病肾病（DN）小鼠炎症的保护作用。方法:采用高脂饲料喂养联合腹腔注射链脲佐菌素建立DN小鼠模型，造模成功后将野生型（WT）和NRG4基因敲除（KO）小鼠分为WT-DN+绿色荧光蛋白（D-WT-GFP）组、KO-DN+绿色荧光蛋白（D-KO-GFP）组、KO-DN+NRG4（D-KO-NRG4）组，D-WT-GFP组和D-KO-GFP组在小鼠肩胛间区棕色脂肪一次性注射腺相关病毒绿色荧光蛋白，D-KO-NRG4组注射腺相关病毒转录NRG4。另设普通饲料喂养WT小鼠作为对照组（WT-CON）。每组6只。8周实验结束后，检测各组小鼠糖化血红蛋白（H...
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| Published in | 中华糖尿病杂志 Vol. 15; no. 2; pp. 152 - 159 |
|---|---|
| Main Authors | , , , , , , |
| Format | Journal Article |
| Language | Chinese |
| Published |
南方医科大学第一临床医学院，广州 510515%解放军中部战区总医院内分泌科，武汉 430070
01.02.2023
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| Subjects | |
| Online Access | Get full text |
| ISSN | 1674-5809 |
| DOI | 10.3760/cma.j.cn115791-20220510-00208 |
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| Abstract | 目的:探讨棕色脂肪源性神经调节蛋白4（NRG4）对糖尿病肾病（DN）小鼠炎症的保护作用。方法:采用高脂饲料喂养联合腹腔注射链脲佐菌素建立DN小鼠模型，造模成功后将野生型（WT）和NRG4基因敲除（KO）小鼠分为WT-DN+绿色荧光蛋白（D-WT-GFP）组、KO-DN+绿色荧光蛋白（D-KO-GFP）组、KO-DN+NRG4（D-KO-NRG4）组，D-WT-GFP组和D-KO-GFP组在小鼠肩胛间区棕色脂肪一次性注射腺相关病毒绿色荧光蛋白，D-KO-NRG4组注射腺相关病毒转录NRG4。另设普通饲料喂养WT小鼠作为对照组（WT-CON）。每组6只。8周实验结束后，检测各组小鼠糖化血红蛋白（HbA
1c）、血清甘油三酯（TG）、总胆固醇（TC）、游离脂肪酸（FFA）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）、尿白蛋白/肌酐比值（UACR）、血清白细胞介素（IL）-1β、IL-6和肿瘤坏死因子-α（TNF-α）等指标。采用过碘酸希夫染色和电镜观察足细胞损伤情况及肾组织病理改变。采用免疫组织化学法检测肾组织F4/80表达。采用实时荧光定量聚合酶链反应分析各组小鼠肾组织
IL-1β、
IL-6、
TNF-α mRNA表达量。采用Western blotting法检测D-KO-GFP组与D-KO-NRG4组小鼠各组织NRG4蛋白表达水平。采用单因素方差分析比较组间差异。采用Pearson相关分析法分析血清NRG4水平与血清炎症因子、UACR、肾组织F4/80表达的相关性。
结果:与D-WT-GFP组相比，D-KO-GFP组小鼠UACR明显升高（
P<0.01），肾小球面积增大，系膜基质增生和足细胞损伤，血清IL-1β、IL-6、TNF-α水平显著升高且肾组织中
IL-1β、
IL-6、
TNF-α的mRNA表达也升高（
P<0.01），同时肾组织F4/80表达增加（
P<0.01）。此外，与D-WT-GFP组相比，D-KO-GFP组小鼠HbA
1c、TG、TC、FFA、LDL-C水平升高且体重增加（
P<0.01）。而与D-KO-GFP组相比，D-KO-NRG4组小鼠UACR水平降低（
P<0.01），肾脏炎症指标F4/80表达降低（
P<0.01），HbA
1c、TG、TC、FFA、LDL-C水平下降且体重降低（
P<0.01）。Pearson相关分析结果显示，血清NRG4与IL-1β、IL- |
|---|---|
| AbstractList | 目的:探讨棕色脂肪源性神经调节蛋白4（NRG4）对糖尿病肾病（DN）小鼠炎症的保护作用。方法:采用高脂饲料喂养联合腹腔注射链脲佐菌素建立DN小鼠模型，造模成功后将野生型（WT）和NRG4基因敲除（KO）小鼠分为WT-DN+绿色荧光蛋白（D-WT-GFP）组、KO-DN+绿色荧光蛋白（D-KO-GFP）组、KO-DN+NRG4（D-KO-NRG4）组，D-WT-GFP组和D-KO-GFP组在小鼠肩胛间区棕色脂肪一次性注射腺相关病毒绿色荧光蛋白，D-KO-NRG4组注射腺相关病毒转录NRG4。另设普通饲料喂养WT小鼠作为对照组（WT-CON）。每组6只。8周实验结束后，检测各组小鼠糖化血红蛋白（HbA
1c）、血清甘油三酯（TG）、总胆固醇（TC）、游离脂肪酸（FFA）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）、尿白蛋白/肌酐比值（UACR）、血清白细胞介素（IL）-1β、IL-6和肿瘤坏死因子-α（TNF-α）等指标。采用过碘酸希夫染色和电镜观察足细胞损伤情况及肾组织病理改变。采用免疫组织化学法检测肾组织F4/80表达。采用实时荧光定量聚合酶链反应分析各组小鼠肾组织
IL-1β、
IL-6、
TNF-α mRNA表达量。采用Western blotting法检测D-KO-GFP组与D-KO-NRG4组小鼠各组织NRG4蛋白表达水平。采用单因素方差分析比较组间差异。采用Pearson相关分析法分析血清NRG4水平与血清炎症因子、UACR、肾组织F4/80表达的相关性。
结果:与D-WT-GFP组相比，D-KO-GFP组小鼠UACR明显升高（
P<0.01），肾小球面积增大，系膜基质增生和足细胞损伤，血清IL-1β、IL-6、TNF-α水平显著升高且肾组织中
IL-1β、
IL-6、
TNF-α的mRNA表达也升高（
P<0.01），同时肾组织F4/80表达增加（
P<0.01）。此外，与D-WT-GFP组相比，D-KO-GFP组小鼠HbA
1c、TG、TC、FFA、LDL-C水平升高且体重增加（
P<0.01）。而与D-KO-GFP组相比，D-KO-NRG4组小鼠UACR水平降低（
P<0.01），肾脏炎症指标F4/80表达降低（
P<0.01），HbA
1c、TG、TC、FFA、LDL-C水平下降且体重降低（
P<0.01）。Pearson相关分析结果显示，血清NRG4与IL-1β、IL- |
| Abstract_FL | Objective:To investigate whether brown adipose-derived neuregulin 4 (NRG4) can alleviate diabetic nephropathy (DN) through inhibiting renal inflammatory response.Methods:DN model in mice was induced by high-fat diet feeding combined with intraperitoneal injection of streptozotocin. After the model establishment, wild-type (WT) and NRG4 knockout (KO) mice were divided into WT-DN+green fluorescent protein group (D-WT-GFP), KO-DN+green fluorescent protein group (D-KO-GFP) and KO-DN+NRG4 group (D-KO-NRG4). Then, adeno-associated virus green fluorescent protein or adeno-associated virus NRG4 transcription was injected into the brown adipose tissue in the interscapular region of mice. WT mice feeding normal chow diet were used as control group (WT-CON) (6 mice in each group). After 8 weeks of the experiment, glycated hemoglobin A
1c (HbA
1c), triglyceride (TG), total cholesterol (TC), free fatty acid (FFA), low-density lipoprotein cholesterol (LDL-C), the ratio of urinary microalbumin to urine creatinine (UACR), serum interleukin-1 β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were detected. The pathological glomerular changes and podocyte injury were observed by periodic acid Schiff staining and transmission electron microscopy. The expression of F4/80 in renal tissues was measured by immunohistochemistry. The mRNA of
IL-1β,
IL-6 and
TNF-α in renal tissue were analyzed by real-time quantitative polymerase chain reaction. The expression level of NRG4 protein in multiple tissues of D-KO-GFP group and D-KO-NRG4 group was detected by Western blotting. One-way analysis of variance (ANOVA) was used for comparison between groups. Pearson correlation analysis was used to analyze the correlation of serum NRG4 and the expression of serum inflammatory factors, UACR and F4/80 in renal tissue.
Results:Compared with D-WT-GFP group, UACR was significantly increased in D-KO-GFP group (
P<0.01), glomerular volume and mesangial matrix hyperplasia increased and podocyte injury, serum levels of IL-1β, IL-6 and TNF-α were significantly increased, and mRNA expression of these inflammatory genes in renal tissue was also increased (all
P<0.01), and the expression of F4/80 in renal tissue increased (
P<0.01). In addition, compared with the D-WT-GFP group, in the D-KO-GFP group, the HbA
1c, TG, TC, FFA, LDL-C and body weight increased (all
P<0.01). Compared with D-KO-GFP group, D-KO-NRG4 group significantly decreased UACR level (
P<0.01) and the expression of renal inflammation index F4/80 was decreased (
P<0.01), the HbA
1c, TG, TC, FFA, LDL-C and body weight reduced (all
P<0.01). Pearson correlation analysis showed that serum NRG4 was negatively correlated with the expression of IL-1β, IL-6, TNF-α, UACR and F4/80 in renal tissue (
r=-0.548, -0.637, -0.553, -0.503, -0.554, all
P<0.05). Western blotting results showed that the expression level of NRG4 protein in brown fat of D-KO-NRG4 group was higher, but the expression level of NRG4 protein in liver, kidney, skeletal muscle and white fat was lower (all
P<0.05).
Conclusion:Brown adipose-derived NRG4 can reduce renal inflammatory response, proteinuria and renal injury in DN mice. |
| Author | 丁胜 何凯悦 徐金玲 徐晓丽 向光大 石凌峰 童佳悦 |
| AuthorAffiliation | 南方医科大学第一临床医学院，广州 510515%解放军中部战区总医院内分泌科，武汉 430070 |
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| Author_FL | Ding Sheng Tong Jiayue Xiang Guangda Xu Jinling He Kaiyue Xu Xiaoli Shi Lingfeng |
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| Author_xml | – sequence: 1 fullname: 童佳悦 – sequence: 2 fullname: 徐金玲 – sequence: 3 fullname: 丁胜 – sequence: 4 fullname: 徐晓丽 – sequence: 5 fullname: 何凯悦 – sequence: 6 fullname: 石凌峰 – sequence: 7 fullname: 向光大 |
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| Keywords | 糖尿病肾病 Neuregulin 4 棕色脂肪 炎症 神经调节蛋白4 Diabetic nephropathy Brown adipose tissue Inflammation |
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| PublicationTitle | 中华糖尿病杂志 |
| PublicationTitle_FL | Chinese Journal of Diabetes Mellitus |
| PublicationYear | 2023 |
| Publisher | 南方医科大学第一临床医学院，广州 510515%解放军中部战区总医院内分泌科，武汉 430070 |
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