线粒体DNA及其呼吸链产物在阿霉素肾病中存在缺陷。

Mitochondrial DNA and its respiratory chain products are defective in doxorubicin nephrosis.

作者信息

Lebrecht Dirk, Setzer Bernhard, Rohrbach Rolf, Walker Ulrich A

机构信息

Department of Rheumatology and Clinical Immunology, Albert-Ludwigs University, Freiburg, Germany.

出版信息

Nephrol Dial Transplant. 2004 Feb;19(2):329-36. doi: 10.1093/ndt/gfg564.

DOI:10.1093/ndt/gfg564

PMID:14736955

Abstract

BACKGROUND

Doxorubicin induces a self-perpetuating nephropathy characterized by early glomerular and late-onset tubular lesions in rats. We investigated the potential role of mitochondrial injury in the onset of these lesions.

METHODS

Rats were treated with intravenous doxorubicin (1 mg kg(-1) week(-1)) for 7 weeks and were sacrificed either 1 week ('short-term') or 30 weeks ('long-term') following the last dose. Additional rats received a single dose either 6 days or 2 h prior to euthanasia. All rats were killed at 48 weeks of age. Glomerular and tubular injury was monitored and correlated to the activity or expression of respiratory chain components. Finally, we quantified both nuclear and mitochondrial DNA (mtDNA) as well as superoxide production and the 4834 base pair 'common' mtDNA deletion.

RESULTS

The 'long-term' group had significant glomerular and tubular lesions, depressed activities of mtDNA-encoded NADH dehydrogenase and cytochrome-c oxidase (COX) and increased citrate synthase activity. In addition, expression of the mtDNA-encoded COX subunit I was reduced and mtDNA levels were decreased. In 'short-term' rats, there were fewer tubular lesions, but similar numbers of glomerular lesions activity. Among all animals, glomerular and tubular injury were inversely correlated with mtDNA levels, mtDNA-encoded respiratory chain activities and with the expression of the mtDNA-encoded respiratory chain subunit COX-I. Injury was positively correlated with superoxide production and the activities of nucleus-encoded mitochondrial or cytoplasmic enzymes. Kidneys from the 'long-term' group showed more mtDNA deletions than in 'short-term' animals and these were not observed in the other groups.

CONCLUSIONS

These results suggest an important role for quantitative and qualitative mtDNA alterations through the reduction of mtDNA-encoded respiratory chain function and induction of superoxide in doxorubicin-induced renal lesions.

摘要

背景

阿霉素可诱发一种持续性肾病，其特征为大鼠早期出现肾小球病变，后期出现肾小管病变。我们研究了线粒体损伤在这些病变发生过程中的潜在作用。

方法

大鼠静脉注射阿霉素（1毫克/千克/周），持续7周，在最后一剂注射后1周（“短期”）或30周（“长期”）处死。另外一些大鼠在安乐死之前6天或2小时接受单次剂量注射。所有大鼠均在48周龄时处死。监测肾小球和肾小管损伤情况，并将其与呼吸链成分的活性或表达进行关联分析。最后，我们对核DNA和线粒体DNA（mtDNA）、超氧化物生成量以及4834碱基对的“常见”mtDNA缺失进行了定量分析。

结果

“长期”组出现显著的肾小球和肾小管病变，mtDNA编码的NADH脱氢酶和细胞色素c氧化酶（COX）活性降低，柠檬酸合酶活性增加。此外，mtDNA编码的COX亚基I的表达减少，mtDNA水平降低。“短期”大鼠的肾小管病变较少，但肾小球病变数量和活性相似。在所有动物中，肾小球和肾小管损伤与mtDNA水平、mtDNA编码的呼吸链活性以及mtDNA编码的呼吸链亚基COX-I的表达呈负相关。损伤与超氧化物生成以及核编码的线粒体或细胞质酶的活性呈正相关。“长期”组大鼠肾脏中的mtDNA缺失比“短期”动物更多，其他组未观察到这种情况。