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

Autor:	Fedeles BI; Departments of Biological Engineering, Chemistry and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139., Bhardwaj R; Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, CT 06510., Ishikawa Y; Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, CT 06510., Khumsubdee S; Departments of Biological Engineering, Chemistry and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139.; Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand., Krappitz M; Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, CT 06510., Gubina N; Departments of Biological Engineering, Chemistry and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139.; Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino 142290, Russia., Volpe I; Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, CT 06510., Andrade DC; Departments of Biological Engineering, Chemistry and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139., Westergerling P; Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, CT 06510., Staudner T; Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, CT 06510., Campolo J; Departments of Biological Engineering, Chemistry and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139., Liu SS; Departments of Biological Engineering, Chemistry and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139., Dong K; Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, CT 06510., Cai Y; Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, CT 06510., Rehman M; Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, CT 06510., Gallagher AR; Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, CT 06510., Ruchirawat S; Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand., Croy RG; Departments of Biological Engineering, Chemistry and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139., Essigmann JM; Departments of Biological Engineering, Chemistry and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139., Fedeles SV; Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, CT 06510., Somlo S; Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, CT 06510.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Jan 23; Vol. 121 (4), pp. e2317344121. Date of Electronic Publication: 2024 Jan 19.
DOI:	10.1073/pnas.2317344121
Abstrakt:	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. Competing Interests: Competing interests statement:The patent US9982009 was granted to B.I.F., R.G.C., J.M.E., S.V.F., and S.S., and assigned to Massachusetts Institute of Technology and Yale University. The patent covers the use of the 11beta-dipropyl and related compounds as therapeutics for polycystic kidney disease and polycystic liver disease. All other authors declare no competing interests.
Databáze:	MEDLINE
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