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A Novel High-Content Screening Assay Identified Belinostat as Protective in a FSGS-Like Zebrafish Model
Maximilian Schindler1, Florian Siegerist1, Tim Lange1
1Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany.
Background:
FSGS affects the complex three-dimensional morphology of podocytes, resulting in loss of filtration barrier function and the development of sclerotic lesions. Therapies to treat FSGS are limited, and podocyte-specific drugs are unavailable. To address the need for treatments to delay or stop FSGS progression, researchers are exploring the repurposing of drugs that have been approved by the US Food and Drug Administration (FDA) for other purposes.
Methods:
To identify drugs with potential to treat FSGS, we used a specific zebrafish screening strain to combine a high-content screening (HCS) approach with an in vivo model. This zebrafish screening strain expresses nitroreductase and the red fluorescent protein mCherry exclusively in podocytes (providing an indicator for podocyte depletion), as well as a circulating 78 kDa vitamin D-binding enhanced green fluorescent protein fusion protein (as a readout for proteinuria). To produce FSGS-like lesions in the zebrafish, we added 80 µ M metronidazole into the fish water. We used a specific screening microscope in conjunction with advanced image analysis methods to screen a library of 138 drugs and compounds (including some FDA-approved drugs) for podocyte-protective effects. Promising candidates were validated to be suitable for translational studies.
Results:
After establishing this novel in vivo HCS assay, we identified seven drugs or compounds that were protective in our FSGS-like model. Validation experiments confirmed that the FDA-approved drug belinostat was protective against larval FSGS. Similar pan-histone deacetylase inhibitors also showed potential to reproduce this effect.
Conclusions:
Using an FSGS-like zebrafish model, we developed a novel in vivo HCS assay that identified belinostat and related pan-histone deacetylase inhibitors as potential candidates for treating FSGS.
Insights
Researchers screened FDA-approved drugs using a zebrafish model to find treatments for Focal Segmental Glomerulosclerosis (FSGS). They identified belinostat and related compounds as promising candidates to protect podocytes and slow FSGS progression.
Area of Science:
- Nephrology
- Drug Discovery
- Zebrafish Models
Background:
- Focal Segmental Glomerulosclerosis (FSGS) damages podocytes, leading to kidney scarring and filtration loss.
- Current FSGS therapies are limited, with no specific drugs targeting podocytes.
- Drug repurposing offers a strategy to find new treatments for FSGS.
Purpose of the Study:
- To develop and implement a high-content screening (HCS) assay in zebrafish to identify drugs that protect podocytes.
- To screen a library of compounds, including FDA-approved drugs, for efficacy against FSGS-like pathology.
- To validate promising drug candidates for potential translation to human FSGS treatment.
Main Methods:
- Established a novel zebrafish strain expressing fluorescent markers in podocytes for monitoring cell health and proteinuria.
- Induced FSGS-like lesions in zebrafish using metronidazole exposure.
- Conducted an in vivo HCS assay screening 138 drugs and compounds for podocyte-protective effects.
Main Results:
- Successfully developed and validated a novel in vivo HCS assay for FSGS drug discovery.
- Identified seven protective drugs/compounds from the screened library.
- Confirmed that the FDA-approved drug belinostat demonstrated significant protective effects against larval FSGS.
Conclusions:
- The developed zebrafish HCS assay is a powerful tool for identifying FSGS therapeutics.
- Belinostat and other pan-histone deacetylase inhibitors show significant potential for treating FSGS.
- These findings pave the way for further investigation and clinical translation of novel FSGS treatments.
