非诺贝特及罗格列酮对高糖培养肾小球系膜细胞p38MAPK 信号通路调控影响

中国临床药理学与治疗学 ›› 2009, Vol. 14 ›› Issue (5): 509-514.

非诺贝特及罗格列酮对高糖培养肾小球系膜细胞p38MAPK 信号通路调控影响

倪连松, 金洁娜, 郑景晨, 沈飞霞

温州医学院附属第一医院内分泌科, 温州325000, 浙江

收稿日期:2008-12-22 修回日期:2009-05-15 发布日期:2020-11-09
通讯作者: 倪连松, 男, 副主任医师, 硕士研究生导师, 主要从事糖尿病肾病发病机理及治疗研究。Tel:13758876020 E-mail:nils1014 @163.com
基金资助:
温州市科技局资助项目(Y20060066);省留学回国基金资助项目(2005HG01)

Effects of fenofibrate and rosiglitazone on the signal passway of p38MAPK in glomerular mesangial cells cultivated in high concentration of glucose

NI Lian-song, JIN Jie-na, ZHENG Jing-chen, SHEN Fei-xia

Department of Endocrinology, First Affiliated Hospital of Wenzhou Medical College, Wenzhou 325000, Zhejiang, China

Received:2008-12-22 Revised:2009-05-15 Published:2020-11-09

摘要/Abstract

摘要： 目的:探讨非诺贝特及罗格列酮对高糖培养大鼠肾小球系膜细胞(MC)p38 丝裂原活化蛋白激酶(p38MAPK)信号传导通路的影响。方法:大鼠系膜细胞分别培养在正常糖浓度(5. 5 mmol/L)、高糖浓度(25 mmol/L)、25 mmol/L葡萄糖+非诺贝特(FB)100 μmol/L 及25 mmol/L葡萄糖+罗格列酮(RG)20 μmol/L 。ELISA 法检测培养细胞上清液Ⅳ型胶原(Col-Ⅳ)、纤维连接蛋白(FN);Phospho-ELISA 法检测胞浆及胞核内p38MAPK 和磷酸化p38MAPK(p-p38MAPK)蛋白的表达;以及RT-PCR 法检测p38MAPK 的mRNA 的表达。结果:与正常对照组比较, 高糖组MC 合成基质蛋白Col-Ⅳ、 FN 增多;胞浆及胞核内pp38MAPK的表达增加。非诺贝特及罗格列酮干预能使高糖培养系膜细胞合成Col-Ⅳ、 FN 显著减少, 胞核内p-p38MAPK 表达显著下调, 但对胞浆内p-p38MAPK 的表达则无显著影响。各组总p38MAPK 蛋白水平及p38MAPK 的mRNA 表达则没有明显改变。结论:非诺贝特及罗格列酮能够显著下调高糖培养的MC 核内p38MAPK 信号传导通路的活化, 进而减少胞外基质合成。

关键词: 非诺贝特, 罗格列酮, 肾小球系膜细胞, p38 丝裂原活化蛋白激酶, 糖尿病肾病

Abstract: AIM:To investigate the effects of fenofibrate (FB)and rosiglitazone(RG)on the signal passway of p38 mitogen-activated protein kinases (p38 MAPK)in glomerular mesangial cells cultivated in high concentration of glucose. METHODS:Rat mesangial cells(MC)were incubated in 5. 5 mmol/L normal control glucose, 25 mmol/L high glucose (HG), HG + 100 μmol/L fenofibrate (FB +HG), HG +20 μmol/L rosiglitazone maleate (RG +HG), respectively. The fibronectin (FN)and type Ⅳ collagen (Col-Ⅳ)in supernatant were determined by ELISA. The expressions of p38MAPK and phospho-p38MAPK proteins in cytoplasm and nuclei were detected by Phospho-ELISA. The mRNA expression of p38MAPK was detected by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR).RESULTS:Compared with normal control, the Col-Ⅳand FN in supernatant in HG group were much higher, the expression of p-p38MAPK was increased in cytoplasms and nuclei. Col-Ⅳ and FN were obviously decreased with the treatment of FB or RG, and the expression of p-p38MAPK in nuclei was down-regulated, but the expression of p-p38MAPK in intracytoplasm had no changes. There were no significant differences of the expressions of total protein and mRNA of p38MAPK among four groups. CONCLUSION: FB, RG could inhibit the activation of p38MAPK in nuceli of MC cultivated in high concentration of glucose, and then reduce the synthesis of extracellular matrix.

Key words: fenofibrate, rosiglitazone, mesangial cells, p38 mitogen-activated protein kinases (p38 MAPK), diabetic nephropathy

中图分类号:

R965. 2

倪连松, 金洁娜, 郑景晨, 沈飞霞. 非诺贝特及罗格列酮对高糖培养肾小球系膜细胞p38MAPK 信号通路调控影响[J]. 中国临床药理学与治疗学, 2009, 14(5): 509-514.

NI Lian-song, JIN Jie-na, ZHENG Jing-chen, SHEN Fei-xia. Effects of fenofibrate and rosiglitazone on the signal passway of p38MAPK in glomerular mesangial cells cultivated in high concentration of glucose[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2009, 14(5): 509-514.

参考文献

[1] Yamashita H, Nagai Y, Takamura T, et al.Thiazolidinedione derivatives ameliorate albuminuria in streptozotocininduced diabetic spontaneous hypertensive rat[J]. Metabolism, 2002, 51(4):403-408.
[2] Ko GJ, Kang YS, Han SY, et al. Pioglitazone attenuates diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats[J]. Nephrol Dial Transplant, 2008, 23(9):2750-2760.
[3] Bakris G, Viberti G, Weston WM, et al.Rosiglitazone reduces urinary albumin excretion in type 2 diabetes[J]. J Hum Hypertens, 2003, 17(1):7-12.
[4] Varghese Z, Moorhead JF, Ruan XZ.The PPARalpha ligand fenofibrate: meeting multiple targets in diabetic nephropathy[J]. Kidney Int, 2006, 69(9):1511-1517.
[5] Staels B, Fruchart JC.Therapeutic roles of peroxisome proliferator-activated receptor agonists [J]. Diabetes, 2005, 54(8):2460-2470.
[6] Shanmugam N, Reddy MA, Guha M. High glucose-induced expression ofproinflammatory cytokine and chemokine genes in monocytic cells[J]. Diabetes, 2003, 52 (5):1256-1264.
[7] Park CW, Zhang Y, Zhang X, et al.PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice [J]. Kidney Int, 2006, 69(9):1490-1491.
[8] Park CW, Kim HW, Ko SH, et al. Accelerated diabetic nephropathy in mice lacking the peroxisome proliferatoractivated receptor alpha[J]. Diabetes, 2006, 55(4):885-893.
[9] Zafiriou S, Stanners SR, Saad S, et al.Pioglitazone in hibits cell growth and reduces matrix production in human kidney fibroblasts [J]. J Am Soc Nephrol, 2005, 16(3): 638-645.
[10] Jiang Y.Characterization of the structure and function of fourth member of p38 group mitogen-activated protein kinase p38delta[J]. J Biol Chem, 1997, 272(48):30122- 30128.
[11] Adhikary L, Chow F, Nikolic-Paterson DJ, et al. Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy[J]. Diabetologia, 2004, 47(7):1210^-1222.
[12] Tsiani E, Lekas P, Fantus IG, et al. High glucose-enhanced activation of mesangial cell p38 MAPK by ET-1, ANG II, and platelet-derived growth factor[J]. Am J Physiol EndocrinolMetab, 2002, 282(1):E161-E169.
[13] Hǜll M, Lieb K, Fiebich BL.Pathways of inflammatory activation in Alzheimer's disease: potential targets for disease modifying drugs[J]. Curr Med Chem, 2002, 9(1): 83-88.
[14] Xing B, Xin T, Hunter RL, et al.Pioglitazone inhibition of lipopolysaccharide-induced nitric oxide synthase is associated with altered activity of p38 MAP kinase and PI3K/Akt[J]. J Neuroinflammation, 2008, 18(5):4.

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