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Title: The role of Prostaglandin E2 in the pathogenesis of Autosomal Dominant Polycystic Kidney Disease
Author: Abdelaali, Fatma
ISNI:       0000 0004 5923 6210
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2016
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Rationale & Hypothesis: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common genetic cause of end stage renal disease (ESRD). Cyst formation in ADPKD requires epithelial cell proliferation and fluid secretion into closed cyst cavities. These effects are mediated mainly by elevated intracellular cAMP levels which induce both cell proliferation and increased fluid secretion. Prostaglandin E2 (PGE2) has been shown to increase intracellular cAMP levels and we and others have shown that its receptor (PTGER2) is increased in renal cyst epithelia possibly leading to increases in cAMP levels in these cells. This study was designed to test the hypothesis that blocking PGE2 activation might have a therapeutic role in reducing cyst growth in ADPKD. Methodology: Taqman qPCR, Western blotting, immunohistochemistry and ELISA for cAMP level were used to determine the expression of PTGER2 and PTGER4 in normal and ADPKD samples. Kidney epithelial cells derived from patients with ADPKD, non-ADPKD controls and MDCK cells were tested for their ability to form cysts or tubules in 3D cultures using a variety of extracellular matrices. The effect of selective PTGER2 and PTGER4 antagonists on cystogenesis was determined in 3D cultures. Furthermore, I tested the effect of PGE2, PTGER2 and PTGER4 antagonist on cell proliferation and apoptosis. Levels of intracellular cAMP in cystic human cells, and control cells were measured by commercial ELISA assays. Results: PTGER2 mRNA and protein levels were significantly increased in cells and tissue sections derived from patients with ADPKD compared to normal controls and also in inducible kidney specific PKD1 knock-out mouse models compared to wild-type littermates. In human 3D cyst assays, PTGER2 and PTGER4 antagonists inhibited cytogenesis in a dose dependent manner. Furthermore, PTGER2 and PTGER4 antagonists inhibited cystic cell proliferation and increased apoptosis compared to the control cells. Conclusions: These results suggest that the use of specific PTGER2 and PTGER4 receptor antagonists could be effective in slowing cyst growth in human ADPKD.
Supervisor: Ong, Albert ; Streets, Andrew Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available