Targeting methylglyoxal in diabetic kidney disease using the novel mitochondria-targeted compound MitoGamide

Diabetic kidney disease (DKD) remains the number one cause of end-stage renal disease in the western world. Currently there is no treatment to cure diabetes or deal effectively with its complications. In experimental diabetes, mitochondrial dysfunction in the kidney has been widely reported with changes in mitochondrial bioenergetics preceding the development of the renal lesion. Glucose-derived molecules generated during diabetes, known as dicarbonyls, such as methylglyoxal, are thought to impair mitochondrial function and may contribute to the pathogenesis of DKD. Here, we sought to target methylglyoxal within the mitochondria using MitoGamide, the novel mitochondria-targeted dicarbonyl scavenger, in an experimental model of diabetes. Male 6-week-old heterozygous Akita mice (C57BL/6-Ins2-Akita/J) or wildtype littermates were randomized to receive MitoGamide (10mg/kg/day) or vehicle by oral gavage for 16 weeks. MitoGamide did not alter blood glucose control or body composition. Akita mice exhibited hallmarks of DKD including albuminuria, hyperfiltration, glomerulosclerosis and renal fibrosis, however, after 16 weeks of treatment, MitoGamide did not substantially improve the renal phenotype. Complex-I-linked mitochondrial respiration was increased in the kidney of Akita mice which was unaffected by MitoGamide. Exploratory studies using transcriptomics identified that MitoGamide induced changes to olfactory signalling, immune system, respiratory electron transport and post-translational protein modification pathways. These findings indicate that targeting methylglyoxal within the mitochondria using MitoGamide is not a valid therapeutic approach for DKD and that other mitochondrial targets or processes upstream should be the focus of therapy. Overall design: Heterozygous Ins2-Akita mice (C57BL/6J-Ins2Akita) and their wild type littermates underwent treatment with mitoGamide or mitoQ or their respective vehicle controls at 6 weeks of age via oral gavage. The treatment was continued until mice were 22 weeks of age, at which time the kidneys were harvested and renal cortex tissue underwent RNA extraction and sequencing. Only male mice were used.

糖尿病肾病（Diabetic kidney disease, DKD）仍是西方世界终末期肾病的首要致病原因。目前尚无治愈糖尿病或有效应对其并发症的治疗手段。在实验性糖尿病模型中，肾脏线粒体功能障碍已被广泛报道，且肾损伤发生前就已出现线粒体生物能学（mitochondrial bioenergetics）的改变。糖尿病进程中产生的葡萄糖衍生分子——即二羰基化合物（dicarbonyls），如甲基乙二醛（methylglyoxal），被认为会损伤线粒体功能，可能参与糖尿病肾病的发病机制。本研究旨在通过新型线粒体靶向二羰基清除剂MitoGamide，在糖尿病实验模型中靶向线粒体内部的甲基乙二醛。将6周龄的雄性杂合型Akita小鼠（C57BL/6-Ins2-Akita/J）及其野生型同窝小鼠随机分组，通过灌胃给予MitoGamide（10mg/kg/天）或赋形剂，持续干预16周。MitoGamide未对血糖控制水平或身体组成产生影响。Akita小鼠表现出糖尿病肾病的典型特征，包括白蛋白尿（albuminuria）、高滤过（hyperfiltration）、肾小球硬化（glomerulosclerosis）及肾纤维化（renal fibrosis）；但经16周治疗后，MitoGamide未显著改善肾脏表型。Akita小鼠肾脏中复合物I（Complex-I）依赖的线粒体呼吸功能增强，该变化不受MitoGamide干预。转录组学（transcriptomics）探索性研究显示，MitoGamide可诱导嗅觉信号通路、免疫系统、呼吸电子传递及蛋白质翻译后修饰（post-translational protein modification）通路发生改变。本研究结果表明，通过MitoGamide靶向线粒体内部的甲基乙二醛并非糖尿病肾病的有效治疗策略，治疗应聚焦于其他线粒体靶点或上游通路。总体实验设计：6周龄的雄性杂合型Ins2-Akita小鼠（C57BL/6J-Ins2Akita）及其野生型同窝小鼠，通过灌胃分别给予MitoGamide、MitoQ或其对应的赋形剂对照，治疗持续至小鼠22周龄时处死取材，收集肾脏并提取肾皮质组织RNA进行测序。本研究仅使用雄性小鼠。