mTOR信号通路调控糖尿病肾病肾小球肥大的机制及中药的干预作用
代表性的下游信号分子是4E结合蛋白（4E-binding proteins，4EBP）和70 kD核糖体S6激酶（phosphoprotein 70 S6Kinase，p70S6K）。一些中药提取物可以在体外通过干预PI3K/Akt/mTOR信号通路关键上、下游信号分子的表达而改善细胞增殖。对于肾小球系膜细胞和足细胞，mTOR通过调节细胞周期、能量代谢以及相关的基质蛋白合成等多种途径对肾小球固有细胞发挥着重要的调控作用。对于DN动物模型，mTOR抑制剂——雷帕霉素可抑制肾小球固有细胞肥大、增殖以及相应的肾小球基底膜增厚和系膜基质沉积。一些中药提取物在体内外可以通过干预DN肾组织或肾脏固有细胞mTOR信号通路的活性而减轻相应的肾小球病变。
[关键词]糖尿病肾病;中药;肾小球肥大;mTOR信号通路
Regulative mechanisms of mammalian target of rapamycin signaling pathway
in glomerular hypertrophy in diabetic nephropathy and interventional effects of
Chinese herbal medicine
YANG Jing-jing1， HUANG Yan-ru 2， WAN Yi-gang3 *， SHEN Shan-mei4， MAO Zhi-min1， WU Wei1， YAO Jian2
（1. Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine， Nanjing University of
Chinese Medicine， Nanjing 210029， China;
2.Department of Molecular Signaling University of Yamanashi， Yamanashi 409-3898， Japan;
3.Nanjing Drum Tower Hospital， The Affiliated Hospital of Nanjing University Medical School， Department of
Traditional Chinese Medicine， Nanjing 210008， China;
4.Nanjing Drum Tower Hospital， The Affiliated Hospital of Nanjing University Medical School， Department of
endocrinology， Nanjing 210008， China）
[Abstract]Glomerular hypertrophy is the main pathological characteristic in the early stage of diabetic nephropathy（DN）， and its regulatory mechanism is closely related to mammalian target of rapamycin（mTOR） signaling pathway activity. mTOR includes mTOR complex 1（mTORC1）and mTOR complex 2（mTORC2）， in which， the upstream pathway of mTORC1 is phosphatidylinositol-3-kinase（PI3K）/serine-threonine kinase（Akt）/adenosine monophosphate activated protein kinase（AMPK）， and the representative signaling molecules in the downstream pathway of mTORC1 are 4E-binding proteins（4EBP）and phosphoprotein 70 S6Kinase（p70S6K）. Some Chinese herbal extracts could improve cell proliferation via intervening the expressions of the key molecules in the upstream or downstream of PI3K/Akt/mTOR signaling pathway in vivo. As for glomerular mesangial cells（MC）and podocyte， mTOR plays an important role in regulating glomerular inherent cells， including adjusting cell cycle， energy metabolism and matrix protein synthesis. Rapamycin， the inhibitor of mTOR， could suppress glomerular inherent cell hypertrophy， cell proliferation， glomerular basement membrane（GBM）thickening and mesangial matrix deposition in model rats with DN. Some Chinese herbal extracts could alleviate glomerular lesions by intervening mTOR signaling pathway activity in renal tissue of DN animal models or in renal inherent cells in vivo and in vitro.