Document Type

Article

Publication Date

5-6-2019

Identifier

DOI: 10.1371/journal.pone.0216220; PMCID: PMC6502331

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.

Journal Title

PLoS One

Volume

14

Issue

5

First Page

0216220

Last Page

0216220

MeSH Keywords

Active Transport, Cell Nucleus; Animals; Cell Proliferation; Domperidone; Dopamine Antagonists; Drug Evaluation, Preclinical; Epithelial Cells; Histone Deacetylases; Kidney; Mice; Polycystic Kidney, Autosomal Dominant

Keywords

Active Transport, Cell Nucleus; Animals; Cell Proliferation; Domperidone; Dopamine Antagonists; Drug Evaluation, Preclinical; Epithelial Cells; Histone Deacetylases; Kidney; Mice; Polycystic Kidney, Autosomal Dominant

Comments

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Publisher's Link: https://doi.org/10.1371/journal.pone.0216220

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