Rodríguez-Mañas L, Sánchez-Rodríguez C, Vallejo S, El-Assar M, Peiró C, Azcutia V, Matesanz N, Sánchez-Ferrer C F, Nevado J
Unidad de Investigación, Hospital Universitario de Getafe, Getafe, Madrid, Spain.
Br J Pharmacol. 2006 Dec;149(8):979-87. doi: 10.1038/sj.bjp.0706864. Epub 2006 Oct 30.
Diabetes mellitus is prevalent in the elderly population. It is also a disease causing tissue damage through several different mechanisms. Some of these mechanisms are also activated by ageing and this overlap raises questions about how diabetes induces damage in the elderly. Early products of non-enzymatic glycation of proteins (Amadori adducts), and the ageing process share the capacity to induce oxidative stress and inflammation in human peritoneal mesothelial cells (HPMCs). We have evaluated the interactions between the age of the donor of the HPMCs and the pro-inflammatory effects of Amadori adducts in those cells.
HPMCs were isolated from 20 individuals (age range 21-81 years) and grown in culture. Using different experimental approaches we determined NF-kappaB dependent transcriptional activity and different NF-kappaB-related pro-inflammatory gene and protein expressions in basal (or non-stimulated) conditions and after stimulation with two Amadori adducts; highly-glycated haemoglobin and glycated bovine serum albumin.
Amadori-induced effects on NF-kappaB dependent-transcription and on the activity of NOS, COX and several NF-kappaB-related pro-inflammatory genes (iNOS, COX-2, TNF-alpha, IL-1beta, and IL6) diminished as the donor's age increased, being practically absent in cells from donors more than 65 years old. Such decreased effects were inversely correlated with an increased basal expression and activity of these pro-inflammatory markers with age.
Pro-inflammatory effects of Amadori-adducts in HPMCs were strongly dependent on cell donor's age. This may have significant implications for the mechanisms underlying diabetes-induced tissue damage in patients of different ages.
糖尿病在老年人群中普遍存在。它也是一种通过多种不同机制导致组织损伤的疾病。其中一些机制也会因衰老而被激活，这种重叠引发了关于糖尿病如何在老年人中诱导损伤的问题。蛋白质非酶糖基化的早期产物（阿马多里加合物）与衰老过程都具有在人腹膜间皮细胞（HPMC）中诱导氧化应激和炎症的能力。我们评估了HPMC供体年龄与这些细胞中阿马多里加合物促炎作用之间的相互作用。
从20名个体（年龄范围21 - 81岁）中分离出HPMC并在培养中生长。我们使用不同的实验方法，在基础（或未刺激）条件下以及用两种阿马多里加合物（高度糖化血红蛋白和糖化牛血清白蛋白）刺激后，测定了NF-κB依赖性转录活性以及不同的NF-κB相关促炎基因和蛋白质表达。
随着供体年龄的增加，阿马多里加合物对NF-κB依赖性转录以及对一氧化氮合酶（NOS）、环氧化酶（COX）和几种NF-κB相关促炎基因（诱导型一氧化氮合酶（iNOS）、COX-2、肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6））活性的影响减弱，在65岁以上供体的细胞中几乎不存在这种影响。这种减弱的影响与这些促炎标志物随年龄增加的基础表达和活性增加呈负相关。
阿马多里加合物在HPMC中的促炎作用强烈依赖于细胞供体的年龄。这可能对不同年龄患者中糖尿病诱导的组织损伤机制具有重要意义。
