Study on the pathological role of AGEs in renal diseases

AGEs在肾脏疾病中的病理作用研究

• 批准号: 09044280
• 负责人: MIYATA Toshio
• 金额: $ 2.82万
• 依托单位: Tokai University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09044280/
• 关键词: Oxidative stress; Carbonyl stress; AGEs; Renal failure; Reduction and oxidation; Diabetes mellitus; Pentosidine

Proteins are modified with advanced glycation end products (AGEs) formed by non - enzymatic glycation and oxidation (glycoxidation) reaction. Research on AGEs in human pathology initially focused on diabetes with sustained hyperglycemia. Recent studies, however, demonstrated the increased AGE genesis in normoglycemic uremia and atherosclerosis. Their AGE accumulation cannot be attributed to hyperglycemia. Gathered evidence has suggested that, under oxidative stress, the increased carbonyl compounds, derived from both carbohydrates and lipids, modify proteins by not only glycoxidation reaction but also lipoxidation reaction, leading to formation of not only AGEs but also advanced lipoxidation end products (ALEs). Thus, the pathological lesions might be in a state of carbonyl overload with potentially damaging proteins ("carbonyl stress"). The increased AGEs/ALEs in tissue proteins may betray abroad derangement in non - enzymatic biochemistry involving both carbohydrates and lipids. Immu … More nohistochemical studies with specific antibodies to AGEs /ALEs, identified "carbonyl stress" in human atherosclerosis, diabetic nephropathy, uremic dialysis related amyloidosis._Proteins modified with AGEs/ALEs exhibited various biological effects on several types of cells. The carbonyl compounds per se crosslink matrix proteins and alter their structure and function. They further interact with cell surface proteins, transduce the intracellular signaling, and induce cellular responses. These biological activities might account in part for the pathology.We recently found a novel compound that inhibits the carbonyl stress and AGE/ALE formation. This compound inhibits the intracellular protein - tyrosine phosphorylation in cultured cells exposed to carbonyl compounds. Oral administration of the compound in a rat carotid artery balloon injury model effectively inhibited the neointimal proliferation. These findings suggest the usefulness of carbonyl compound entrapping in the treatment of the diseases. Less

蛋白质被非酶糖基化和氧化（糖氧化）反应形成的晚期糖基化终产物（AGEs）修饰。AGEs在人类病理中的研究最初集中在持续高血糖的糖尿病上。然而，最近的研究表明，在血糖正常的尿毒症和动脉粥样硬化中AGE的发生增加。他们的AGE积累不能归因于高血糖。已有证据表明，在氧化应激下，来源于碳水化合物和脂质的羰基化合物增加，不仅通过糖氧化反应，也通过脂氧化反应修饰蛋白质，导致AGEs和晚期脂氧化终产物（ALEs）的形成。因此，病理病变可能处于羰基超载状态，具有潜在的破坏性蛋白质（“羰基应激”）。组织蛋白中AGEs/ALEs的增加可能暴露了碳水化合物和脂类非酶生化的严重紊乱。更多针对AGEs /ALEs特异性抗体的组织化学研究发现，在人类动脉粥样硬化、糖尿病肾病、尿毒症透析相关淀粉样变性中存在“羰基应激”。_用AGEs/ALEs修饰的蛋白对不同类型的细胞表现出不同的生物学效应。羰基化合物本身交联基质蛋白质并改变其结构和功能。它们进一步与细胞表面蛋白相互作用，转导细胞内信号，并诱导细胞反应。这些生物活动可能部分解释了病理。我们最近发现了一种抑制羰基应激和AGE/ALE形成的新化合物。这种化合物抑制暴露于羰基化合物的培养细胞中的细胞内蛋白酪氨酸磷酸化。在大鼠颈动脉球囊损伤模型中口服该化合物可有效抑制新内膜增殖。这些发现提示羰基化合物包埋在疾病治疗中的有用性。少

项目成果

Toshio Miyata: "Implication of altered redox regulation by antioxidant enzymes in the increased plasma pentosidine, an advanced glycation end product, in uremia." Biochem Biophys Res Commun. 245. 785-790 (1998)

Toshio Miyata：“尿毒症患者血浆戊糖苷（一种晚期糖基化终产物）增加中抗氧化酶氧化还原调节改变的影响。”

Toshio Miyata: "Neurotoxicity of methylglyxal and 3-Deoxyglycose on cultured cortical neurons : Synergism between glycation and oxidative stress, possibly involved in neurodegnerative diseases." Neurosci letter. (in press).

Toshio Miyata：“甲基乙醛和 3-脱氧糖对培养的皮质神经元的神经毒性：糖化和氧化应激之间的协同作用，可能与神经退行性疾病有关。”

Toshio Miyata: "Oxidative stress and long-term complications of uremia." Kidney International. (in press).

Toshio Miyata：“氧化应激和尿毒症的长期并发症。”

Toshio Miyata: "Altered non-enzymatic biochemistry in uremia involving carbohydrates and lipids." Nephrol Dial Transplant. (in press).

Toshio Miyata：“改变尿毒症中涉及碳水化合物和脂质的非酶生物化学。”

Toshio Miyata: "Carbonyl stress diabetic nephropathy." Jpn J Nephrol. in press.

Toshio Miyata：“羰基应激性糖尿病肾病。”