Division of Nephrology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
Nephrology (Carlton). 2011 May;16(4):417-25. doi: 10.1111/j.1440-1797.2010.01437.x.
The authors recently showed that advanced glycation end-products (AGE) in the form of glycated albumin (GA) upregulated renal tubular expression of interleukin (IL)-8 and soluble intercellular adhesion molecule-1 (sICAM-1), but not other important cytokines known to mediate diabetic nephropathy. This implies that other molecules such as the carbonyl intermediates of AGE or other modified protein lysine-albumin may participate in diabetic tubular injury.
Human proximal tubular epithelial cells (PTEC) were growth-arrested and exposed to methylglyoxal (MG), MG-bovine serum albumin (BSA)-AGE, carboxymethyllysine (CML)-BSA, AGE-BSA or BSA with or without prior addition of rosiglitazone that was previously shown to attenuate the pro-inflammatory effect of GA alone.
MG-BSA-AGE and AGE-BSA upregulated tubular expression of connective tissue growth factor (CTGF), transforming growth factor (TGF)-β, and vascular endothelial growth factor (VEGF), whereas CML-BSA stimulated expression of IL-6, CCL-2, CTGF, TGF-β and VEGF. These AGE compounds also activated nuclear factor (NF)-κB and their effects were attenuated by pre-incubation with anti-RAGE antibody. MG and BSA did not affect the expression of any of these molecules. Rosiglitazone did not affect the in vitro biological effects of MG, MG-BSA-AGE, AGE-BSA or CML-BSA on PTEC.
AGE exhibit differential inflammatory and fibrotic effects on PTEC via RAGE activation and NF-κB signal transduction. Rosiglitazone had no effect on these responses. Further investigations on compounds that nullify the downstream effects of these AGE are warranted.
作者最近表明，以糖化白蛋白（GA）形式存在的晚期糖基化终产物（AGE）上调了肾小管细胞中白细胞介素（IL）-8 和可溶性细胞间黏附分子-1（sICAM-1）的表达，但不影响其他介导糖尿病肾病的重要细胞因子。这意味着其他分子，如 AGE 的羰基中间产物或其他修饰的蛋白赖氨酸-白蛋白，可能参与了糖尿病肾小管损伤。
将人近端肾小管上皮细胞（PTEC）生长抑制并暴露于甲基乙二醛（MG）、MG-牛血清白蛋白（BSA）-AGE、羧甲基赖氨酸（CML）-BSA、AGE-BSA 或 BSA 中，同时或不预先加入罗格列酮，先前的研究表明罗格列酮可以减弱 GA 单独的促炎作用。
MG-BSA-AGE 和 AGE-BSA 上调了结缔组织生长因子（CTGF）、转化生长因子（TGF）-β和血管内皮生长因子（VEGF）的肾小管表达，而 CML-BSA 刺激了 IL-6、CCL-2、CTGF、TGF-β和 VEGF 的表达。这些 AGE 化合物还激活了核因子（NF）-κB，并且它们的作用可以通过预先孵育抗 RAGE 抗体来减弱。MG 和 BSA 均不影响这些分子的表达。罗格列酮对 MG、MG-BSA-AGE、AGE-BSA 或 CML-BSA 对 PTEC 的体外生物学作用没有影响。
AGE 通过 RAGE 激活和 NF-κB 信号转导对 PTEC 表现出不同的炎症和纤维化作用。罗格列酮对这些反应没有影响。需要进一步研究能够消除这些 AGE 下游作用的化合物。
