Extracellular nucleotides, such as ATP and UTP, are now widely accepted as regulators of diverse cellular functions including regulation of ion transport in epithelial tissues. They signal via multiple P2 receptor subtypes. Current evidence suggests that P2 receptors are expressed in kidney epithelia and that they may influence transport of ions and fluid. Consequently, alterations in the physiology of P2 receptor signalling may be involved in the development of renal diseases such as autosomal dominant polycystic kidney disease (ADPKD), an inherited kidney disease in which abnormal cell physiology is thought to contribute to disease progression. In this thesis, the expression and role of P2 receptors in the kidney and their possible influence on ADPKD cyst growth have been investigated. Several P2 receptor subtypes were identified on specific cells of the normal rat kidney. Mostly P2Y receptors were detected in the glomerulus and tubule epithelium, but also P2Xs receptors were found on collecting duct cells and P2X4 and P2X6 receptors were expressed at a low level throughout the nephron. The P2Y1,2,4,6 and the P2X5 and P2X7 subtypes were detected on the cyst lining cells of (cy/+) rat polycystic kidneys, and P2Y2,6 and P2X7 receptor mRNA was increased when compared to normal rat kidneys. P2X7 receptor expression was also increased in rodent models of glomerular injury. In vitro, inhibition of mostly P2Y receptor subtypes with antagonists or removal of ATP from the growth medium significantly reduced the growth of MDCK microcysts. This work has extended the current knowledge of P2 receptor expression in healthy and diseased kidney tissue. The pattem of P2 receptor expression in renal cysts indicate that these receptors may play a role in cyst formation and progression. Their influence is most likely via ATP-stimulated chloride secretion and accelerated proliferation of epithelial cells; both of which are key factors that affect ADPKD cyst growth. These findings support the hypothesis for a role of P2 receptors in renal cyst growth and enlargement. However, these initial observations require more study, since there are many P2 receptor subtypes, one of which might prove to be a therapeutic target to limit cyst growth and preserve renal function.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:416934 |
| Date | January 2005 |
| Creators | Turner, Clare Marie |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1446663/ |
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