Format

Send to

Choose Destination
PLoS One. 2019 May 6;14(5):e0216220. doi: 10.1371/journal.pone.0216220. eCollection 2019.

Dopamine receptor antagonists as potential therapeutic agents for ADPKD.

Author information

1
Center for Cell Dynamics, Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
2
Stowers Institute for Medical Research, Kansas City, MO, United States.
3
Division of Neonatology, Children's Mercy Hospital, Kansas City, MO, United States.
4
Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, United States.

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is caused mostly by mutations in polycystin-1 or polycystin-2. Fluid flow leads to polycystin-dependent calcium influx and nuclear export of histone deacetylase 5 (HDAC5), which facilitates the maintenance of renal epithelial architecture by de-repression of MEF2C target genes. Here, we screened a small-molecule library to find drugs that promotes nuclear export of HDAC5. We found that dopamine receptor antagonists, domperidone and loxapine succinate, stimulate export of HDAC5, even in Pkd1-/-cells. Domperidone targets Drd3 receptor to modulate the phosphorylation of HDAC5. Domperidone treatment increases HDAC5 phosphorylation likely by reducing protein phosphatase 2A (PP2A) activity, thus shifting the equilibrium towards HDAC5-P and export from the nucleus. Treating Pkd1-/-mice with domperidone showed significantly reduced cystic growth and cell proliferation. Further, treated mice displayed a reduction in glomerular cyst and increased body weight and activity. These results suggest that HDAC5 nucleocytoplasmic shuttling may be modulated to impede disease progression in ADPKD and uncovers an unexpected role for a class of dopamine receptors in renal epithelial morphogenesis.

PMID:
31059522
DOI:
10.1371/journal.pone.0216220
Free full text

Conflict of interest statement

The authors have declared that no competing interests exist.

Supplemental Content

Full text links

Icon for Public Library of Science
Loading ...
Support Center