Chemical modifier screen identifies HDAC inhibitors as suppressors of PKD models.
Polycystic kidney disease (PKD) is a common human genetic disease with severe medical consequences. Although it is appreciated that the cilium plays a central role in PKD, the underlying mechanism for PKD remains poorly understood and no effective treatment is available. In zebrafish, kidney cyst formation is closely associated with laterality defects and body curvature. To discover potential drug candidates and dissect signaling pathways that interact with ciliary signals, we performed a chemical modifier screen for the two phenotypes using zebrafish pkd2(hi4166) and ift172(hi2211) models. pkd2 is a causal gene for autosomal dominant PKD and ift172 is essential for building and maintaining the cilium. We identified trichostatin A (TSA), a pan-HDAC (histone deacetylase) inhibitor, as a compound that affected both body curvature and laterality. Further analysis verified that TSA inhibited cyst formation in pkd2 knockdown animals. Moreover, we demonstrated that inhibiting class I HDACs, either by valproic acid (VPA), a class I specific HDAC inhibitor structurally unrelated to TSA, or by knocking down hdac1, suppressed kidney cyst formation and body curvature caused by pkd2 deficiency. Finally, we show that VPA was able to reduce the progression of cyst formation and slow the decline of kidney function in a mouse ADPKD model. Together, these data suggest body curvature may be used as a surrogate marker for kidney cyst formation in large-scale high-throughput screens in zebrafish. More importantly, our results also reveal a critical role for HDACs in PKD pathogenesis and point to HDAC inhibitors as drug candidates for PKD treatment.
Cao
Ying
Y
Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Semanchik
Nicole
N
Lee
Seung Hun
SH
Somlo
Stefan
S
Barbano
Paolo Emilio
PE
Coifman
Ronald
R
Sun
Zhaoxia
Z
D000818:Animals; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D005799:Genes, Dominant; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000235:genetics; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D010641:Phenotype; D007690:Polycystic Kidney Diseases / Q000188:drug therapy* / Q000235:genetics; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use; D015027:Zebrafish
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D014635:Valproic Acid; D006655:Histone Deacetylases