Proteomics Reveals Novel Oxidative and Glycolytic Mechanisms in Type 1 Diabetic Patients' Skin Which Are Normalized by Kidney-Pancreas Transplantation
Proteomics Reveals Novel Oxidative and Glycolytic Mechanisms in Type 1 Diabetic Patients' Skin Which Are Normalized by Kidney-Pancreas Transplantation
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DOI：
10.1371/journal.pone.0009923
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发表时间：
2010-03-29
期刊：
影响因子：
3.7
通讯作者：
Fiorina, Paolo
中科院分区：
文献类型：
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作者：
Folli, Franco;Guzzi, Valeria;Fiorina, Paolo
工作背景：在1型糖尿病（T1 D）中，血管并发症如加速动脉粥样硬化和弥漫性大/微血管病变与慢性高血糖症有关，其机制尚未完全了解。终末期肾病（ESRD）的糖尿病并发症，特别是，从心血管疾病的发病率和死亡率的风险增加了几倍，方法和结果：我们评估了蛋白质的调节和表达，从T1 D患者和没有ESRD皮肤活检，以确定与糖尿病血管疾病的持续细胞变化的途径。因此，我们研究的途径，可以通过恢复正常的肾胰腺（KP）移植。利用蛋白质组学和超微结构的方法，在参与氧化应激的蛋白质表达的多种改变，（过氧化氢酶、超氧化物歧化酶1、Hsp 27、Hsp 60、ATP合成酶δ链和黄素还原酶）、有氧和无氧糖酵解（ACBP，丙酮酸激酶肌肉同工酶和磷酸甘油酸激酶1）和细胞内信号传导在T1 D和T1 D +ESRD患者中发现了血管内皮细胞异常（分层蛋白-14-3-3，S100-钙周期蛋白，组织蛋白酶和PPI旋转酶）以及内皮血管异常。这些异常在KP移植后逆转。在T1 D和T1 D +ESRD患者中观察到血浆丙二醛水平升高，证实氧化应激增加，KP transplant.Conclusions后恢复正常：我们的数据表明，持续的细胞变化的抗氧化机制和有氧/无氧糖酵解存在于T1 D和T1 D +ESRD患者，这些异常可能发挥关键作用的高血糖症相关的血管并发症的发病机制。肾移植后恢复正常肾功能和清除尿毒症可纠正这些异常。其中一些已确定的途径可能成为新一代药物的潜在治疗靶点。
Background: In type 1 diabetes (T1D) vascular complications such as accelerated atherosclerosis and diffused macro-/microangiopathy are linked to chronic hyperglycemia with a mechanism that is not yet well understood. End-stage renal disease (ESRD) worsens most diabetic complications, particularly, the risk of morbidity and mortality from cardiovascular disease is increased several fold.Methods and Findings: We evaluated protein regulation and expression in skin biopsies obtained from T1D patients with and without ESRD, to identify pathways of persistent cellular changes linked to diabetic vascular disease. We therefore examined pathways that may be normalized by restoration of normoglycemia with kidney-pancreas (KP) transplantation. Using proteomic and ultrastructural approaches, multiple alterations in the expression of proteins involved in oxidative stress (catalase, superoxide dismutase 1, Hsp27, Hsp60, ATP synthase delta chain, and flavin reductase), aerobic and anaerobic glycolysis (ACBP, pyruvate kinase muscle isozyme, and phosphoglycerate kinase 1), and intracellular signaling (stratifin-14-3-3, S100-calcyclin, cathepsin, and PPI rotamase) as well as endothelial vascular abnormalities were identified in T1D and T1D+ESRD patients. These abnormalities were reversed after KP transplant. Increased plasma levels of malondialdehyde were observed in T1D and T1D+ESRD patients, confirming increased oxidative stress which was normalized after KP transplant.Conclusions: Our data suggests persistent cellular changes of anti-oxidative machinery and of aerobic/anaerobic glycolysis are present in T1D and T1D+ESRD patients, and these abnormalities may play a key role in the pathogenesis of hyperglycemia-related vascular complications. Restoration of normoglycemia and removal of uremia with KP transplant can correct these abnormalities. Some of these identified pathways may become potential therapeutic targets for a new generation of drugs.