Dopamine receptor antagonists as potential therapeutic agents for ADPKD.
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-re...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2019-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0216220 |
| _version_ | 1819044187989868544 |
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| author | Parama Paul Sreekumar Ramachandran Sheng Xia Jay R Unruh Juliana Conkright-Fincham Rong Li |
| author_facet | Parama Paul Sreekumar Ramachandran Sheng Xia Jay R Unruh Juliana Conkright-Fincham Rong Li |
| author_sort | Parama Paul |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T10:08:42Z |
| format | Article |
| id | doaj.art-e5399717e0b5480f90d8c9fb16d26725 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T10:08:42Z |
| publishDate | 2019-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-e5399717e0b5480f90d8c9fb16d267252022-12-21T19:07:47ZengPublic Library of Science (PLoS)PLoS ONE1932-62032019-01-01145e021622010.1371/journal.pone.0216220Dopamine receptor antagonists as potential therapeutic agents for ADPKD.Parama PaulSreekumar RamachandranSheng XiaJay R UnruhJuliana Conkright-FinchamRong LiAutosomal 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.https://doi.org/10.1371/journal.pone.0216220 |
| spellingShingle | Parama Paul Sreekumar Ramachandran Sheng Xia Jay R Unruh Juliana Conkright-Fincham Rong Li Dopamine receptor antagonists as potential therapeutic agents for ADPKD. PLoS ONE |
| title | Dopamine receptor antagonists as potential therapeutic agents for ADPKD. |
| title_full | Dopamine receptor antagonists as potential therapeutic agents for ADPKD. |
| title_fullStr | Dopamine receptor antagonists as potential therapeutic agents for ADPKD. |
| title_full_unstemmed | Dopamine receptor antagonists as potential therapeutic agents for ADPKD. |
| title_short | Dopamine receptor antagonists as potential therapeutic agents for ADPKD. |
| title_sort | dopamine receptor antagonists as potential therapeutic agents for adpkd |
| url | https://doi.org/10.1371/journal.pone.0216220 |
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