HDAC5-mediated regulation in autosomal dominant polycystic kidney disease

Paul, Parama (2015). HDAC5-mediated regulation in autosomal dominant polycystic kidney disease. Doctor of Philosophy (PhD) thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000f686

Abstract

Maintenance of epithelial tubular structure is important for proper renal function. Disruption of this process has been implicated in autosomal dominant polycystic kidney disease (ADPKD). ADPKD is caused by mutation in the Pkd1 or Pkd2 gene, which encode polycystins (PC1 and PC2). Mutations in PC1 and PC2 disrupt the mechanosensory function and thus its downstream HDAC5 shuttling. HDAC5 undergoes nuclear export in response to fluid flow. However, in polycystin deficient cells this process is impaired. Previous studies have shown that genetic or chemical inhibition of HDAC can suppress cyst formation in embryonic Pkd2–/– mice. The aim of this study was to investigate the pathways that regulate HDAC5 function downstream of polycystins and can be used as a therapy in ADPKD patients. Initially we used a drug screen to find drugs that can cause nuclear export of HDAC5 in absence of fluid-flow. We found that dopamine antagonists, such as domperidone and loxapine succinate, can cause HDAC5 nuclear export downstream of polycystin and in a cilia-independent manner. Further, our studies also show that domperidone can reduce cyst formation or progression in Pkd1–/– postnatal mice and this correlates well with reduction in cell proliferation. Next we sought to investigate the complex that HDAC5 forms in renal epithelial cells. HDAC5 binds HDAC3, a class I HDAC, and TBLR1 to form an enzymatically active complex. Thus therapeutically targeting HDAC3 or TBLR1 can be used as an alternative treatment approach for ADPKD. Thirdly, we performed microarray analysis to compare gene expression levels in Hdac5-/- to Hdac5+/+ cells. We found that HDAC5-regulated MEF2C target genes, Cxcl1 and Paip1, are upregulated when HDAC5 is inhibited. These genes can be therapeutic targets for treating ADPKD. The focus of this thesis is a comprehensive study of the different aspects of HDAC5 regulation and its potential implication in treating ADPKD.

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