MethylMalonic Acidemia (MMA) is predicted by lipocalin-2 (LCN2) and attenuated by antioxidant therapy

Isolated methylmalonic acidemia (MMA) is a pleiotropic enzymatic defect of branched-chain amino acid oxidation most commonly caused by deficiency of methylmalonyl-CoA mutase (MUT). End stage renal disease (ESRD) is emerging as an inevitable disease-related complication, recalcitrant to conventional therapies and liver transplantation. To establish a viable model of MMA-associated renal disease, methylmalonyl-CoA mutase (Mut) was expressed in the liver of Mut -/- mice as a stable transgene under the control of an albumin (INS-Alb-Mut) promoter. Mut -/- ;TgINS-Alb-Mut mice were rescued from the neonatal lethality displayed by Mut -/- mice and manifested a decreased glomerular filtration rate (GFR), chronic tubulointerstital nephritis (CTIN) and prominent ultrastructural changes in the proximal tubular mitochondria, replicating precisely the renal manifestations seen in a large MMA patient cohort. To explore the pathophysiological changes that underlie the renal disease of MMA, we compared gene expression profiles of whole kidney mRNA samples between 4 female Mut +/+, Mut +/- and Mut -/- ;TgINS-Alb-Mut mice after they ingested a HP diet for 2 months. Females were used because more survived the dietary challenge, whereas the histology, ultrastructure and GFR effects were identical between sexes孤立性甲基丙二酸血症（methylmalonic acidemia, MMA）是一种多效性支链氨基酸氧化代谢酶缺陷病，最常见的致病原因为甲基丙二酰辅酶A变位酶（methylmalonyl-CoA mutase, MUT）缺乏。终末期肾病（end stage renal disease, ESRD）是该疾病不可避免的并发症，对常规治疗及肝移植均难以奏效。为构建可用于研究的甲基丙二酸血症相关性肾病模型，我们将甲基丙二酰辅酶A变位酶（Mut）以白蛋白启动子（INS-Alb-Mut）调控的稳定转基因形式，在Mut基因敲除（Mut -/-）小鼠的肝脏中进行表达。结果显示，Mut -/- ;TgINS-Alb-Mut小鼠可摆脱Mut -/-小鼠所表现出的新生致死表型，同时表现为肾小球滤过率（glomerular filtration rate, GFR）降低、慢性肾小管间质性肾炎（chronic tubulointerstitial nephritis, CTIN），以及近端肾小管线粒体出现显著超微结构改变，精准复现了大型甲基丙二酸血症患者队列中观察到的肾脏表型。为探究甲基丙二酸血症肾病的潜在病理生理机制，我们对4只雌性Mut野生型（Mut +/+）、杂合子（Mut +/-）及Mut -/- ;TgINS-Alb-Mut小鼠的全肾mRNA样本进行了基因表达谱比较分析，这些小鼠在喂食高蛋白（HP）饲料2个月后。本研究选用雌性小鼠，是因为更多个体可耐受该饮食干预，且不同性别间的组织学、超微结构及GFR改变并无差异。