Nadaraja, S.P.; (2011) Regulation of pathways involved in intestinal phosphate transport. Doctoral thesis , UCL (University College London).

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Abstract

Despite the importance of extracellular phosphate, the mechanisms and control of intestinal phosphate transport remain unclear. The present study used in vivo and in vitro methods to compare the extent of Na+- dependent versus Na+-independent phosphate transport along the rat small intestine and colon at different luminal phosphate concentrations. Na+-dependent and Na+-independent phosphate transport and genomic expression of type II (NaPi-II) and type III (PiT) transporters in young (3- week old) and adult (8- and 16-week old) animals fed a control or low phosphate diet have also been quantified. mRNA levels of Na+- dependent phosphate transporters have been analysed in the 5/6 nephrectomy model of chronic renal failure and following treatment with matrix extracellular phosphoglycoprotein (MEPE). The acute effects of altered luminal phosphate concentration on intestinal phosphate transport and renal phosphate transporter expression was also assessed. The findings confirm the jejunum to be the main site of Na+-dependent phosphate absorption under both normal and low dietary phosphate conditions. Low phosphate diet upregulates Na+-dependent and Na+- independent phosphate transport in both duodenum and jejunum, whereas age only affects Na+-dependent component in the duodenum and jejunum. When luminal phosphate concentrations are in the physiological (millimolar) range, absorption in the jejunum displays less Na+-dependency and is unlikely to be mediated exclusively by the Na+- dependent NaPi-IIb cotransporter. In the ileum, again using millimolar luminal phosphate concentrations, significant Na+-dependent phosphate transport was detected, but the rate of phosphate absorption was lower than in the jejunum. Since NaPi-IIb is not expressed at the rat ileal brush-border membrane (BBM), the presence of significant Na+- dependent phosphate transport suggests an alternative phosphate uptake pathway in the ileum. At millimolar luminal phosphate concentrations in the distal colon, only Na+-independent phosphate absorption was detected. Thus, at concentrations of phosphate normally present in the intestinal lumen, Na+-independent pathways of phosphate absorption are present in the proximal small intestine and distal colon, as well as a non-NaPi-IIb-mediated Na+-dependent pathway in the distal small intestine. PiT2 assumes a dominant role in phosphate transport in the jejunum of pre-weaned animals, and in the kidneys of animals fed a low phosphate diet. PiT1 transporter is not regulated by age or low phosphate diet at the genomic level. Chronic renal failure reduces intestinal and renal expression of the major transporter NaPi-II, and also PiT1 and PiT2. However, MEPE reduces intestinal expression of NaPi-IIb and PiT2 alone in chronic renal failure animals. Acute duodenal instillation of either 15 mM or 1.3 M phosphate did not affect the renal BBM protein expression of NaPi-IIa and NaPi-IIc. Duodenal instillation of 1.3 M, but not 15 mM, phosphate increased phosphate uptake in the duodenum only; however, the small intestine is unlikely to encounter phosphate concentrations in the molar range.

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