Heme oxygenase-1 enhances renal mitochondrial transport carriers and cytochrome c oxidase activity in experimental diabetes
Heme oxygenase-1 enhances renal mitochondrial transport carriers and cytochrome c oxidase activity in experimental diabetes
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DOI：
10.1074/jbc.m510595200
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发表时间：
2006-06-09
影响因子：
4.8
通讯作者：
Abraham, Nader G.
中科院分区：
文献类型：
--
作者：
Di Noia, Maria Antonietta;Van Driesche, Sarah;Abraham, Nader G.
钴原卟啉(CoPP)或人类基因转移上调血红素加氧酶(HO-1)可通过几种机制改善血管和肾功能，包括增加抗氧化剂水平和减少血管和肾组织中的活性氧(ROS)。本研究旨在探讨HO-1过表达对链脲佐菌素(STZ)诱导的1型糖尿病大鼠线粒体转运蛋白、细胞色素C氧化酶和抗细胞凋亡蛋白的影响。糖尿病大鼠肾脏线粒体肉碱、脱氧核苷酸和ADP/ATP载体较非糖尿病大鼠显著减少(p<；0.05)。糖尿病组织中柠檬酸载体的含量没有明显减少。CoPP使肉碱、柠檬酸、脱氧核苷酸、二羧酸盐和ADP/ATP携带者显著增加，而在草戊二酸和天冬氨酸/谷氨酸携带者中无明显变化。线粒体载体(MC)的增加与细胞色素C氧化酶活性的显著增加有关。给予HO-1活性的抑制剂锡中卟啉(SNMP)可阻止糖尿病大鼠肾小球系膜细胞的恢复。人HO-1基因转移到糖尿病大鼠体内可增加HO-1蛋白和活性，恢复线粒体ADP/ATP和脱氧核苷酸载体。COPP对HO-1表达的增加与AKT的磷酸化和bclxl蛋白水平的显著增加有关。这些在实验性糖尿病中的观察结果表明，HO-1对氧化应激的细胞保护机制包括增加MCs和抗凋亡蛋白的水平以及细胞色素c氧化酶的活性。
Up-regulation of heme oxygenase (HO-1) by either cobalt protoporphyrin (CoPP) or human gene transfer improves vascular and renal function by several mechanisms, including increases in antioxidant levels and decreases in reactive oxygen species (ROS) in vascular and renal tissue. The purpose of the present study was to determine the effect of HO-1 overexpression on mitochondrial transporters, cytochrome c oxidase, and anti-apoptotic proteins in diabetic rats ( streptozotocin, (STZ)-induced type 1 diabetes). Renal mitochondrial carnitine, deoxynucleotide, and ADP/ATP carriers were significantly reduced in diabetic compared with nondiabetic rats (p < 0.05). The citrate carrier was not significantly decreased in diabetic tissue. CoPP administration produced a robust increase in carnitine, citrate, deoxynucleotide, dicarboxylate, and ADP/ATP carriers and no significant change in oxoglutarate and aspartate/glutamate carriers. The increase in mitochondrial carriers (MCs) was associated with a significant increase in cytochrome c oxidase activity. The administration of tin mesoporphyrin (SnMP), an inhibitor of HO-1 activity, prevented the restoration of MCs in diabetic rats. Human HO-1 cDNA transfer into diabetic rats increased both HO-1 protein and activity, and restored mitochondrial ADP/ATP and deoxynucleotide carriers. The increase in HO-1 by CoPP administration was associated with a significant increase in the phosphorylation of AKT and levels of BcL-XL proteins. These observations in experimental diabetes suggest that the cytoprotective mechanism of HO-1 against oxidative stress involves an increase in the levels of MCs and anti-apoptotic proteins as well as in cytochrome c oxidase activity.