Vekaria, RM; (2006) The functional role of extracellular nucleotides in the renal tubule. Doctoral thesis , UCL (University College London).

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Abstract

There is increasing evidence that extracellular nucleotides (such as ATP, ADP, UTP and UDP), as well as the nucleoside adenosine, behave as autocrine or paracrine agents in most tissues including the kidney, acting on a group of receptors known as purinoceptors. Previous studies have shown that activation of these receptors by exogenous nucleotides can influence a variety of renal vascular and tubular functions. Purinoceptors of various subtypes are present on basolateral and apical membranes of renal tubules. However, the extent to which apical receptors are stimulated by endogenous nucleotides is unknown. Using micropuncture, the first part of this study quantified endogenous ATP in the lumen of proximal and distal tubules of the rat in vivo, both under control conditions and during pathophysiological manoeuvres. The results showed that ATP levels were sufficiently high to activate some purinoceptor subtypes. To assess whether the intraluminal ATP was being secreted or merely filtered at the glomerulus, the ATP content of fluid from Bowman's space (in Munich-Wistar rats) was compared with that in proximal tubules. The conclusion was that tubular epithelial cells secrete ATP. Using a proximal tubular epithelial cell line, the mechanism of ATP release was examined. Intracellular stores of ATP were visualised using a marker compound (quinacrine), and the fate of these stores was monitored following hypotonic stimulation of ATP release. The findings suggested that ATP is stored within the cytoplasm, possibly in vesicles, and is released by exocytosis. In the final part of the investigation, using immunohistochemistry, the distribution of five nucleotide-hydrolysing ectonucleotidases, namely NTPDases 1-3, NPP3 and ecto-5'- nucleotidase, was examined along the rat nephron. These enzymes (which differ in their hydrolysis pathways) were found to be differentially expressed along the major segments of the nephron, suggesting that they may be strategically located to influence the activity of the different purinoceptor subtypes.

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