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.
Highlights
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common and life-threatening genetic diseases leading to end-stage renal failure, yet to date there are few therapeutic interventions against this disease
We further investigated the mechanism by which dopamine receptor antagonists promotes histone deacetylase 5 (HDAC5) nuclear export and demonstrated the ability of one of these compounds to slow cyst growth in Pkd1–/–mice
Our previous study found that Hdac5 heterozygosity and chemical inhibition by pan-HDAC inhibitor, trichostatin A, reduced cyst formation in Pkd2 –/–mouse embryos [12]
Summary
ADPKD is one of the most common and life-threatening genetic diseases leading to end-stage renal failure, yet to date there are few therapeutic interventions against this disease. Most cases of ADPKD are caused by heterozygous germline mutations in either the Pkd or Pkd gene [1]. PC1 and PC2 interact via their C-terminal tails to form a receptor-calcium channel complex, which some have proposed to sense mechanical stress exerted on renal epithelial cells [2,3,4]. Mouse with homozygous deletion of Pkd die in utero between embryonic day 14.4–15.5 Mouse models of conditional Pkd gene disruption showed that loss of Pkd at 14 days after birth does not cause immediate polycystic phenotype.
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