In vitro 3D phenotypic drug screen identifies celastrol as an effective in vivo inhibitor of polycystic kidney disease

Author:

Booij Tijmen H12ORCID,Leonhard Wouter N3,Bange Hester4,Yan Kuan4,Fokkelman Michiel1,Plugge Anna J3,Veraar Kimberley A M3,Dauwerse Johannes G3,van Westen Gerard J P5,van de Water Bob1,Price Leo S14,Peters Dorien J M3

Affiliation:

1. Division of Toxicology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands

2. NEXUS Personalized Health Technologies, ETH Zürich, Switzerland

3. Department of Human Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands

4. OcellO B.V., Leiden, The Netherlands

5. Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden, The Netherlands

Abstract

Abstract Polycystic kidney disease (PKD) is a prevalent genetic disorder, characterized by the formation of kidney cysts that progressively lead to kidney failure. The currently available drug tolvaptan is not well tolerated by all patients and there remains a strong need for alternative treatments. The signaling rewiring in PKD that drives cyst formation is highly complex and not fully understood. As a consequence, the effects of drugs are sometimes difficult to predict. We previously established a high throughput microscopy phenotypic screening method for quantitative assessment of renal cyst growth. Here, we applied this 3D cyst growth phenotypic assay and screened 2320 small drug-like molecules, including approved drugs. We identified 81 active molecules that inhibit cyst growth. Multi-parametric phenotypic profiling of the effects on 3D cultured cysts discriminated molecules that showed preferred pharmacological effects above genuine toxicological properties. Celastrol, a triterpenoid from Tripterygium Wilfordii, was identified as a potent inhibitor of cyst growth in vitro. In an in vivo iKspCre-Pkd1lox,lox mouse model for PKD, celastrol inhibited the growth of renal cysts and maintained kidney function.

Funder

Dutch Technology Foundation

Netherlands Organization for Scientific Research

EU-FP7—Systems Microscopy NoE

Dutch Kidney Foundation

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Genetics,Molecular Biology,General Medicine

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