A synthetic agent ameliorates polycystic kidney disease by promoting apoptosis of cystic cells through increased oxidative stress

• 成果类型: Article
• 署名作者: Fedeles, Bogdan I.; Bhardwaj, Rishi; Ishikawa, Yasunobu; Khumsubdee, Sakunchai; Krappitz, Matteus; Gubina, Nina; Volpe, Isabel; Andrade, Denise C.; Westergerling, Parisa; Staudner, Tobias; Campolo, Jake; Liu, Sally S.; Dong, Ke; Cai, Yiqiang; Rehman, Michael; Gallagher, Anna-Rachel; Ruchirawat, Somsak; Croy, Robert G.; Essigmann, John M.; V. Fedeles, Sorin; Somlo, Stefan
• 署名单位: Saint Joseph's University; University of Freiburg; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Yale University; Chulabhorn Research Institute; Russian Academy of Sciences; Pushchino Scientific Center for Biological Research (PSCBI) of the Russian Academy of Sciences; Institute of Theoretical & Experimental Biophysics; University of Erlangen Nuremberg
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13995
• DOI: 10.1073/pnas.2317344121
• 发表日期: 2024-01-23
• 关键词: mitochondria; metabolism; 2-deoxy-d-glucose; models; GROWTH

摘要

Autosomal dominant polycystic kidney disease (ADPKD) is the most common mono-genic 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 anti-oxidant 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.