Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia
Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia
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DOI：
10.1073/pnas.1302764110
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发表时间：
2013-08-13
影响因子：
11.1
通讯作者：
Venditti, Charles P.
中科院分区：
文献类型：
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作者：
Manoli, Irini;Sysol, Justin R.;Venditti, Charles P.
分离性甲基丙二酸血症（MMA）是由线粒体酶甲基丙二酰辅酶a突变酶（MUT）缺乏引起的，通常并发终末期肾脏疾病，对包括肝移植在内的常规治疗具有耐药性。为了建立MMA肾脏疾病的可行模型，在白蛋白（INS-Alb-Mut）启动子的控制下，Mut作为稳定的转基因在Mut（-/-）小鼠的肝脏中表达。傻瓜(- / -);Tg（INS-Alb-Mut）小鼠虽然完全摆脱了Mut（-/-）小鼠的新生儿死亡率，但单肾细胞GFR研究表明，它们表现出肾小球滤过率（GFR）下降、慢性小管间质性肾炎和近端小管线粒体超微结构改变，这些改变与小管功能异常有关。Mut（-/-）基因微阵列分析Tg（INS-Alb-Mut）肾脏鉴定出许多生物标志物，包括脂钙素-2，然后用于监测小鼠模型中GFR对抗氧化治疗的反应。来自大量不同患者队列（ClinicalTrials.gov识别号：NCT00078078）的肾脏活检和生物标志物分析精确地复制了动物的发现，建立了Mut(-/-)；Tg（INS-Alb-Mut）小鼠作为MMA肾病的独特模型。我们的研究表明近端小管线粒体功能障碍是MMA相关肾脏疾病的关键致病机制，确定脂钙素-2是肾小管氧化应激增加的生物标志物，并证明抗氧化剂可以减轻MMA肾病。
Isolated methylmalonic acidemia (MMA), caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT), is often complicated by end stage renal disease that is resistant to conventional therapies, including liver transplantation. To establish a viable model of MMA renal disease, Mut was expressed in the liver of Mut(-/-) mice as a stable transgene under the control of an albumin (INS-Alb-Mut) promoter. Mut(-/-);Tg(INS-Alb-Mut) mice, although completely rescued from neonatal lethality that was displayed by Mut(-/-) mice, manifested a decreased glomerular filtration rate (GFR), chronic tubulointerstitial nephritis and ultrastructural changes in the proximal tubule mitochondria associated with aberrant tubular function, as demonstrated by single-nephron GFR studies. Microarray analysis of Mut(-/-);Tg(INS-Alb-Mut) kidneys identified numerous biomarkers, including lipocalin-2, which was then used to monitor the response of the GFR to antioxidant therapy in the mouse model. Renal biopsies and biomarker analysis from a large and diverse patient cohort (ClinicalTrials.gov identifier: NCT00078078) precisely replicated the findings in the animals, establishing Mut(-/-);Tg(INS-Alb-Mut) mice as a unique model of MMA renal disease. Our studies suggest proximal tubular mitochondrial dysfunction is a key pathogenic mechanism of MMA-associated kidney disease, identify lipocalin-2 as a biomarker of increased oxidative stress in the renal tubule, and demonstrate that antioxidants can attenuate the renal disease of MMA.