Pathogenesis of diabetic nephropathy: the role of oxidative stress and protein kinase C
Pathogenesis of diabetic nephropathy: the role of oxidative stress and protein kinase C
复制标题
DOI：
10.1016/s0168-8227(99)00044-3
复制
发表时间：
1999-09-01
影响因子：
5.1
通讯作者：
Kim, KH
中科院分区：
文献类型：
--
作者：
Ha, H;Kim, KH
高血糖是糖尿病长期并发症的一个公认的致病因素，它不仅产生更多的活性氧，而且通过清除酶的糖基化减弱抗氧化机制。因此，氧化应激被认为是糖尿病肾病等并发症的共同致病因素。氧化应激和糖尿病肾病之间的因果关系已经通过以下观察建立：（1）脂质过氧化物和8-羟基脱氧鸟苷（氧化组织损伤的指标）在伴有白蛋白尿的糖尿病大鼠肾脏中增加;（2）高糖直接增加肾小球系膜细胞（糖尿病肾病的靶细胞）的氧化应激;（3）氧化应激诱导TGF-β 1和纤连蛋白的mRNA表达，它们是与糖尿病肾小球损伤有关的基因，和（4）氧化应激的抑制改善了与糖尿病肾病相关的所有表现。与高血糖症相关的氧化应激中涉及的机制是葡萄糖自氧化、高级糖基化终产物的形成和由高血糖症引起的代谢应激。由于蛋白激酶C（PKC）的抑制不仅有效地阻断佛波酯诱导的纤维连接蛋白的产生，而且有效地阻断高糖和H2 O2诱导的纤维连接蛋白的产生，因此糖尿病条件下PKC的激活也可能在糖尿病中氧化应激诱导的肾损伤中具有调节作用。(C)1999爱思唯尔科学爱尔兰有限公司保留所有权利。
Hyperglycemia, a well recognized pathogenetic factor of long-term complications in diabetes mellitus, not only generates more reactive oxygen species but also attenuates antioxidative mechanisms through glycation of the scavenging enzymes. Therefore, oxidative stress has been considered to be a common pathogenetic factor of the diabetic complications including nephropathy. A causal relationship between oxidative stress and diabetic nephropathy has been established by observations that (1) lipid peroxides and 8-hydroxydeoxyguanosine, indices of oxidative tissue injury, were increased in the kidneys of diabetic rats with albuminuria; (2) high glucose directly increases oxidative stress in glomerular mesangial cells, a target cell of diabetic nephropathy; (3) oxidative stress induces mRNA expression of TGF-beta 1 and fibronectin which are the genes implicated in diabetic glomerular injury, and (4) inhibition of oxidative stress ameliorates all the manifestations associated with diabetic nephropathy. Proposed mechanisms involved in oxidative stress associated with hyperglycemia are glucose autooxidation, the formation of advanced glycosylation end products, and metabolic stress resulting from hyperglycemia. Since the inhibition of protein kinase C (PKC) effectively blocks not only phorbol ester-induced but also high glucose- and H2O2-induced fibronectin production, the activation of PKC under diabetic conditions may also have a modulatory role in oxidative stress-induced renal injury in diabetes mellitus. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.