INHIBITION OF PAX2 SUPPRESSES CYST FORMATION IN 3D CULTURE MODELS IN VITRO
Qi Zheng1, Lorissa McDougall1, Cherie Stayner1, Glen Reid1, Mike Eccles1 1University of Otago, Dunedin, Otago, New Zealand
Abstract
Autosomal dominant polycystic kidney disease (ADPKD), with an estimated prevalence between 1:1000 and 1:2500, is one of the most common hereditary kidney diseases in humans. A disease hallmark is the development of hundreds of microscopic fluid-filled cysts in the kidney. The epithelial cells surrounding these cysts show aberrant expression of several developmental genes, including the transcription factor PAX2. In the normal kidney, PAX2 is expressed in developing nephrons but not in adult proximal and distal tubules, whereas polycystic kidney epithelia (and some cancers, including renal cell carcinoma) continue to exhibit high levels of this gene. Many of the nine developmental PAX genes are re-expressed or ectopically expressed in cancer, and in other diseases of abnormal proliferation, making them attractive as tissue-specific therapeutic targets using small molecules. Inhibition of PAX2 activity may be a viable cell-type-specific therapy for cystic kidney disease, especially as downregulation of Pax2 expression in mouse models of ADPKD has resulted in attenuated cyst formation. The use of 3D cell culture models in vitro provides a tractable method to study the development of renal cysts. We have established a Madin-Darby canine kidney cell (MDCK) cyst model and human ADPKD spheroid model, and investigated the effect of inhibiting PAX2 on cyst formation. We found that the small molecule Pax2 inhibitor EG1 significantly suppressed cyst growth and altered features of the cystic phenotype, including inhibition of Pax2-regulated epithelial-mesenchymal transition. These data suggest that targeting Pax2 might be a potential therapeutic strategy for ADPKD.
Biography
Qi ZHENG is a second-year PhD candidate in the Department of Pathology at the University of Otago, where she is researching the role of PAX2 in autosomal dominant polycystic kidney disease. Specifically, her project involves investigating the therapeutic potential of inhibiting PAX2, as well as the underlying functions and signaling pathways involved in the disease.