摘要
糖尿病肾病(DN)是糖尿病主要的微血管并发症。DN的特征包括细胞外基质(ECM)蛋白的积聚,如胶原蛋白、层粘连蛋白和纤维连接蛋白在肾小球系膜区及肾小管-间质和肾小球的基底膜。ECM表达的增加导致肾小球和肾小管基底膜增厚和系膜基质增多,最终使肾小球硬化和肾小管间质纤维化。肾小球系膜病变这一典型的形态学特征被描述为Kimmelstiel–Wilson结节,有时这一过程被称为糖尿病性肾小球硬化。因此,ECM蛋白积累在糖尿病肾病的发生发展中起着至关重要的作用。关于ECM高表达和糖尿病患者肾脏的调节的相关机制已得到广泛的研究和文献记载。然而,还有一些尚未得到确切定义的其他机制。最近的研究表明,一些新的信号通路或分子,如Notch、Wnt、mTOR、Toll样受体与小G蛋白,在糖尿病肾病ECM调控和表达的调节中可能发挥了关键的作用。这种调节是可以控制的,例如:Notch通过Notch1/Jagged1信号通路,Wnt通过Wnt/β-连环蛋白信号通路,mTOR通过PI3-K/Akt/mTOR信号通路调控。所有这些通路可能在ECM表达与肾小管间质纤维化过程中起着关键的调控作用。并且,Toll样受体(主要是TLR2和TLR4),通过TLR2依赖性和TGF-β依赖性的导管, 调节ECM表达并产生纤维化反应。小G蛋白像Rho、Ras及Rab家族一样,针对相关基因也可能影响ECM蛋白和高血糖状态肾纤维化的积累。该综述总结了关于体外和体内状态下这些分子和信号通路调节细胞外基质合成,及其在高血糖环境中的作用和机制的最新信息。对这些影响ECM表达、分泌和积累的信号通路及分子的理解,可能有助于糖尿病肾病治疗策略的改进。
关键词: 糖尿病肾病,细胞外基质,Notch,Wnt,mTOR,Toll样受体,小G蛋白
Current Medicinal Chemistry
Title:Insights into the Mechanisms Involved in the Expression and Regulation of Extracellular Matrix Proteins in Diabetic Nephropathy
Volume: 22 Issue: 24
Author(s): C. Hu, L. Sun, L. Xiao, Y. Han, X. Fu, X. Xiong, X. Xu, Y. Liu, S. Yang, F. Liu and Y.S. Kanwar
Affiliation:
关键词: 糖尿病肾病,细胞外基质,Notch,Wnt,mTOR,Toll样受体,小G蛋白
摘要: Diabetic Nephropathy (DN) is believed to be a major microvascular complication of diabetes. The hallmark of DN includes deposition of Extracellular Matrix (ECM) proteins, such as, collagen, laminin and fibronectin in the mesangium and renal tubulo-interstitium of the glomerulus and basement membranes. Such an increased expression of ECM leads to glomerular and tubular basement membranes thickening and increase of mesangial matrix, ultimately resulting in glomerulosclerosis and tubulointerstitial fibrosis. The characteristic morphologic glomerular mesangial lesion has been described as Kimmelstiel–Wilson nodule, and the process at times is referred to as diabetic nodular glomerulosclerosis. Thus, the accumulation of ECM proteins plays a critical role in the development of DN. The relevant mechanism(s) involved in the increased ECM expression and their regulation in the kidney in diabetic state has been extensively investigated and documented in the literature. Nevertheless, there are certain other mechanisms that may yet be conclusively defined. Recent studies demonstrated that some of the new signaling pathways or molecules including, Notch, Wnt, mTOR, TLRs and small GTPase may play a pivotal role in the modulation of ECM regulation and expression in DN. Such modulation could be operational for instance Notch through Notch1/Jagged1 signaling, Wnt by Wnt/β- catenin pathway and mTOR via PI3-K/Akt/mTOR signaling pathways. All these pathways may be critical in the modulation of ECM expression and tubulo-interstitial fibrosis. In addition, TLRs, mainly the TLR2 and TLR4, by TLR2- dependent and TGF-β-dependent conduits, may modulate ECM expression and generate a fibrogenic response. Small GTPase like Rho, Ras and Rab family by targeting relevant genes may also influence the accumulation of ECM proteins and renal fibrosis in hyperglycemic states. This review summarizes the recent information about the role and mechanisms by which these molecules and signaling pathways regulate ECM synthesis and its expression in high glucose ambience in vitro and in vivo states. The understanding of such signaling pathways and the molecules that influence expression, secretion and amassing of ECM may aid in developing strategies for the amelioration of diabetic nephropathy.
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C. Hu, L. Sun, L. Xiao, Y. Han, X. Fu, X. Xiong, X. Xu, Y. Liu, S. Yang, F. Liu and Y.S. Kanwar , Insights into the Mechanisms Involved in the Expression and Regulation of Extracellular Matrix Proteins in Diabetic Nephropathy, Current Medicinal Chemistry 2015; 22 (24) . https://dx.doi.org/10.2174/0929867322666150625095407
DOI https://dx.doi.org/10.2174/0929867322666150625095407 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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