Possible implication of oxidative damages of mitochondria and mitochondrial DNA in the progressive renal injuries

线粒体和线粒体 DNA 氧化损伤在进行性肾损伤中的可能意义

• 批准号: 13671130
• 负责人: KASHIHARA Naoki
• 金额: $ 0.83万
• 依托单位: KAWASAKI MEDICAL SCHOOL
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671130/
• 关键词: mitochondria; oxidative damage; mitochondrial DNA; reactive oxygen species; 糖尿病; 糖尿病性腎症; 呼吸鎖; アポトーシス

1. Implication of mitochondria and mitochondria injuries in the renal diseases Mitochondria produce most of the cell's energy by oxidative phosphorylation, a process that requires the coordinated actions of five respiratory enzyme complexes located in the mitochondrial inner membrane. On the other hand, emerging evidence demonstrates that mitochondria play a central role in the regulation of apoptosis. Mitochondria are regarded to be essential for cell life and death. We have delineated that oxidative modification of mitochondrial DNA accumulated and was involved in the apoptotic cell death in the process of renal diseases. We investigated the implication of mitochondrial injuries in the progressive forms of renal diseases2. Analysis of genetic background of the patients with renal diseases The mitochondrial DNA is extremely vulnerable to oxidative stress because mitochondria are the major intracellular source of ROS and have limited protection from oxidative stress. We have found increased accumulation of 8- hydroxy- 2^3- deoxyguanosine (8-OHdG), which is a product and biomarker of oxidative DNA damage, in the mitochondria of the renal tissues from patients with chronic renal disease. The hOGGl gene encodes a DNA glycosylase that excises 8- OH- Dg from damaged DNA. Genetic polymorphism of ser (S) 326Cys c has been reported. The enzymatic activity of hOGGl in the repair of 8- OH- Dg has been reported to be greater with S than with C. We found the correlation between hOGGl polymorphism and the clinical phenotype of renal diseases

1. 线粒体和线粒体损伤对肾脏疾病的影响 线粒体通过氧化磷酸化产生大部分细胞能量，这一过程需要位于线粒体内膜的五种呼吸酶复合物的协调作用。另一方面，新出现的证据表明线粒体在细胞凋亡的调节中发挥着核心作用。线粒体被认为对于细胞的生命和死亡至关重要。我们已经阐明线粒体DNA的氧化修饰积累并参与肾脏疾病过程中的细胞凋亡。我们研究了线粒体损伤在进行性肾脏疾病中的影响2。肾病患者遗传背景分析线粒体DNA极易受到氧化应激的影响，因为线粒体是细胞内ROS的主要来源，对氧化应激的保护作用有限。我们发现慢性肾病患者肾组织线粒体中 8-羟基-2^3-脱氧鸟苷 (8-OHdG) 的积累增加，8-OHdG 是氧化 DNA 损伤的产物和生物标志物。 hOGG1基因编码从受损DNA中切除8-OH-Dg的DNA糖基化酶。 Ser (S) 326Cys c 的遗传多态性已被报道。据报道，S 组的 hOGG1 修复 8-OH-Dg 的酶活性高于 C 组。我们发现 hOGG1 多态性与肾脏疾病临床表型之间的相关性

项目成果

Takehiko Tokura, Tamaki Sasaki, Sayaka Arakawa, Naoki Kashihara, et al.: "Transdominant negative FGF receptors inhibit proliferation of cultured glomerular mesangial cells"Kawasaki Medical Jornal. 27. 43-51 (2001)

Takehiko Tokura、Tamaki Sasaki、Sayaka Arakawa、Naoki Kashihara 等人：“反式显性阴性 FGF 受体抑制培养的肾小球系膜细胞的增殖”川崎医学杂志。

堀家英之, 福島達夫, 佐々木環, 藤本壮八, 八田秀一, 柏原直樹 他: "HOGG1遺伝子多型Cys(C)326 Ser(S)とIgA腎症進展との関連"腎とフリーラジカル. 6. 182-187 (2002)

Hideyuki Horie、Tatsuo Fukushima、Tamaki Sasaki、Sohachi Fujimoto、Shuichi Hatta、Naoki Kashihara 等人：“HOGG1 基因多态性 Cys(C)326 Ser(S) 与 IgA 肾病进展之间的关系” 肾脏和自由基 6。 182-187（2002）

Keisuke Maruyama, Naoki Kashihara, Yasushi Yamasaki, Minoru Satoh, etal: "Methylprednisolone Accelerates the Resolution of Glomerulonephritis by Sensitizing Mesangial Cells to Apoptpsis"Exp Nephrol.

Keisuke Maruyama、Naoki Kashihara、Yasushi Yamasaki、Minoru Satoh 等人：“甲基强的松龙通过使系膜细胞对凋亡敏感来加速肾小球肾炎的消退”Exp Nephrol。

柏原直樹, 堀家英之, 藤本壮八, 佐々木環: "糖尿病性腎症"総合臨床. 51・3. 533-539 (2002)

Naoki Kashihara、Hideyuki Horie、Sohachi Fujimoto、Tamaki Sasaki：《糖尿病肾病综合临床实践》51・3（2002）。

Monoru Satoh, Naoki Kashihara, Yasushi Yamasaki, Keisuke Maruyama, et al.: "Renal Intersitial Fibrosis is Reduced in Angiotensin II Type la Receptor-Deficient Mice"J Am Soc Nephrol. 12. 317-325 (2001)

Monoru Satoh、Naoki Kashihara、Yasushi Yamasaki、Keisuke Maruyama 等人：“血管紧张素 II 型 la 受体缺陷小鼠的肾间质纤维化减少”J Am Soc Nephrol。