PDF(Pubmed)
Abstract：
Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of chronic kidney disease and the fourth leading cause of end-stage kidney disease, accounting for over 50% of prevalent cases requiring renal replacement therapy. There is a pressing need for improved therapy for ADPKD. Recent insights into the pathophysiology of ADPKD revealed that cyst cells undergo metabolic changes that up-regulate aerobic glycolysis in lieu of mitochondrial respiration for energy production, a process that ostensibly fuels their increased proliferation. The present work leverages this metabolic disruption as a way to selectively target cyst cells for apoptosis. This small-molecule therapeutic strategy utilizes 11beta-dichloro, a repurposed DNA-damaging anti-tumor agent that induces apoptosis by exacerbating mitochondrial oxidative stress. Here, we demonstrate that 11beta-dichloro is effective in delaying cyst growth and its associated inflammatory and fibrotic events, thus preserving kidney function in perinatal and adult mouse models of ADPKD. In both models, the cyst cells with homozygous inactivation of Pkd1 show enhanced oxidative stress following treatment with 11beta-dichloro and undergo apoptosis. Co-administration of the antioxidant vitamin E negated the therapeutic benefit of 11beta-dichloro in vivo, supporting the conclusion that oxidative stress is a key component of the mechanism of action. As a preclinical development primer, we also synthesized and tested an 11beta-dichloro derivative that cannot directly alkylate DNA, while retaining pro-oxidant features. This derivative nonetheless maintains excellent anti-cystic properties in vivo and emerges as the lead candidate for development.
摘要：
常染色体显性多囊肾病（ADPKD）是慢性肾病最常见的单基因病因，也是终末期肾病的第四大病因，占需要肾脏替代疗法的流行病例的50％以上。迫切需要改善ADPKD的治疗。对ADPKD病理生理学的最新见解表明，囊肿细胞经历代谢变化，从而上调有氧糖酵解，而不是线粒体呼吸来产生能量，表面上助长其扩散的过程。目前的工作利用这种代谢破坏作为选择性靶向囊肿细胞凋亡的方法。这种小分子治疗策略利用11β-二氯，一种再利用的DNA损伤抗肿瘤剂，通过加剧线粒体氧化应激诱导细胞凋亡。这里,我们证明11β-二氯可有效延缓囊肿生长及其相关的炎症和纤维化事件,从而在围产期和成年ADPKD小鼠模型中保留肾功能。在这两种模型中，Pkd1纯合失活的囊肿细胞在用11β-二氯处理后显示出增强的氧化应激并发生凋亡。抗氧化剂维生素E的共同给药否定了体内11β-二氯的治疗益处，支持氧化应激是作用机制的关键组成部分的结论。作为临床前开发的入门,我们还合成并测试了一种不能直接烷基化DNA的11β-二氯衍生物，同时保留促氧化剂的特点。尽管如此，该衍生物在体内仍保持出色的抗囊性能，并成为开发的主要候选者。
