Dopamine receptor antagonists as potential therapeutic agents for ADPKD

Parama Paul, Sreekumar Ramachandran, Sheng Xia, Jay R. Unruh, Juliana Conkright-Fincham, Rong Li

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere0216220
JournalPloS one
Volume14
Issue number5
DOIs
StatePublished - May 7 2019

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Paul, P., Ramachandran, S., Xia, S., Unruh, J. R., Conkright-Fincham, J., & Li, R. (2019). Dopamine receptor antagonists as potential therapeutic agents for ADPKD. PloS one, 14(5), [e0216220]. https://doi.org/10.1371/JOURNAL.PONE.0216220