A high-throughput screening platform for Polycystic Kidney Disease (PKD) drug repurposing utilizing murine and human ADPKD cells.

Scientific Reports
Rosita R AsawaNatalia J Martinez

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited monogenic disorders, characterized by a progressive decline in kidney function due in part to the formation of fluid-filled cysts. While there is one FDA-approved therapy, it is associated with potential adverse effects, and all other clinical interventions are largely supportive. Insights into the cellular pathways underlying ADPKD have revealed striking similarities to cancer. Moreover, several drugs originally developed for cancer have shown to ameliorate cyst formation and disease progression in animal models of ADPKD. These observations prompted us to develop a high-throughput screening platform of cancer drugs in a quest to repurpose them for ADPKD. We screened ~8,000 compounds, including compounds with oncological annotations, as well as FDA-approved drugs, and identified 155 that reduced the viability of Pkd1-null mouse kidney cells with minimal effects on wild-type cells. We found that 109 of these compounds also reduced in vitro cyst growth of Pkd1-null cells cultured in a 3D matrix. Moreover, the result of the cyst assay identified therapeutically relevant compounds, including agents that interfere with tubulin dynamics and reduc...Continue Reading

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Citations

Jul 8, 2020·International Journal of Molecular Sciences·Svenja KoslowskiLaurent Meijer
Jan 5, 2021·Frontiers in Cell and Developmental Biology·Claire E L SmithColin A Johnson
Jun 23, 2021·Biochemical Society Transactions·Taylor RichardsParaskevi Goggolidou
Aug 28, 2021·International Journal of Molecular Sciences·Inês OliveiraMónica Roxo-Rosa
Jun 25, 2021·Journal of the American Society of Nephrology : JASN·Zhiheng LiuYupeng Chen

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Software Mentioned

MatLab script
qHTS
Matplotlib
KNIME analytic platform

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