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Dopamine receptor antagonists as potential therapeutic agents for ADPKD.

Authors :
Parama Paul
Sreekumar Ramachandran
Sheng Xia
Jay R Unruh
Juliana Conkright-Fincham
Rong Li
Source :
PLoS ONE, Vol 14, Iss 5, p e0216220 (2019)
Publication Year :
2019
Publisher :
Public Library of Science (PLoS), 2019.

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.

Subjects

Subjects :
Medicine
Science

Details

Language :
English
ISSN :
19326203
Volume :
14
Issue :
5
Database :
Directory of Open Access Journals
Journal :
PLoS ONE
Publication Type :
Academic Journal
Accession number :
edsdoj.5399717e0b5480f90d8c9fb16d26725
Document Type :
article
Full Text :
https://doi.org/10.1371/journal.pone.0216220