We have demonstrated that the kidney of newborn animals reabsorbs phosphate (Pi) at rates that exceed by 2-fold those observed in adults, that at least two thirds of this difference is accounted for by higher rates of proximal tubular reabsorption of Pi in newborns than in adults, and that the maximal capacity of the Na+- Pi symport system (Vmax) is 4.5-fold higher in renal microvilli from newborn than from adult animals. The abundance of Na+-Pi symporters, estimated from measurements of the maximal Na+- dependent binding of phosphonoformate to renal microvilli, and the intracellular concentration of Pi ([Pi]i), measured by NMR, account only in part, for the difference in Vmax between newborn and mature guinea pigs. On the basis of these findings, we postulate that in growing animals and in rapidly dividing cells of renal origin, the high Vmax of Na+-pi cotransport is due to the combined effects of growth factors such as insulin-like growth factor 1 (IGF1), of 1,25(OH)2D3, and of low [Pi]i, on the functional stimulate Pi efflux form renal tubule cells resulting in a low [Pi]i. Low [Pi]i and 1,25(OH)2D3, in turn, alter the lipid composition, increase the mobility of the Pi cotransporters in the BBM, and induce de novo synthesis of Pi-transport related proteins. Low [Pi]i may also interfere with the activity of protein kinases A or C and account for the unresponsiveness to parathormone (PTH) in rapidly growing cells or animals. In order to test these assumptions we will examine the effects of maneuvers designed to alter the rate of growth (in newborn animals, with an inhibitor of the release of growth hormone; in opposium kidney (OK) cells with growth factors) on the relationships between the Pi supply and: 1) [Pi]i; 2) kinetics (Vmax, Km) for the Na+-Pi cotransport; 3) abundance of Pi transporters, estimated from the maximal Na+-dependent and Pi displaceable binding (Nmax) of phosphonoformate; 4) turnover number of the Pi symporters (Vmax/Nmax), fluidity and lipid composition of the luminal membranes; 5) kinetics of Pi transport across renal cortical basolateral membranes; 6) plasma and tissue levels of 1,25(OH)2D#; 7) activity and subcellular distribution of PKA and PKC; and 8) effect of PTH, c-AMP and phorbol esters on Na+-Pi- contransport. The results of these experiments, should permit us to establish the relationships between [Pi]i and the abundance or the functional activity of the Pi symporters in growing and non- growing animals and renal cells. They should also contribute to the understanding of the role of protein kinases A and C and of vitamin D3 metabolites in the regulation of renal Pi cotransport by growth hormone, insulin like-growth factor, [Pi]i, and PTH.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Barac-Nieto, Mario; Weinman, Edward J; Spitzer, Adrian (2007) Cell-matrix interactions modulate transepithelial phosphate transport in P(i)-deprived OK cells. Am J Physiol Cell Physiol 293:C1272-7
Silverstein, Douglas M; Spitzer, Adrian; Barac-Nieto, Mario (2005) Parathormone sensitivity and responses to protein kinases in subclones of opossum kidney cells. Pediatr Nephrol 20:721-4
Barac-Nieto, M; Alfred, M; Spitzer, A (2002) Basolateral phosphate transport in renal proximal-tubule-like OK cells. Exp Biol Med (Maywood) 227:626-31
Spitzer, A; Barac-Nieto, M (2001) Ontogeny of renal phosphate transport and the process of growth. Pediatr Nephrol 16:763-71
Barac-Nieto, M; Alfred, M; Spitzer, A (2001) Phosphate depletion in opossum kidney cells: apical but not basolateral or transepithelial adaptions of Pi transport. Exp Nephrol 9:258-64
Silverstein, D M; Barac-Nieto, M; Falck, J R et al. (1998) 20-HETE mediates the effect of parathyroid hormone and protein kinase C on renal phosphate transport. Prostaglandins Leukot Essent Fatty Acids 58:209-13
Silverstein, D M; Barac-Nieto, M; Murer, H et al. (1997) A putative growth-related renal Na(+)-Pi cotransporter. Am J Physiol 273:R928-33
Silverstein, D; Barac-Nieto, M; Spitzer, A (1996) Mechanism of renal phosphate retention during growth. Kidney Int 49:1023-6
Barac-Nieto, M; Spitzer, A (1994) NMR-visible intracellular P(i) and phosphoesters during regulation of Na(+)-P(i) cotransport in opossum kidney cells. Am J Physiol 267:C915-9
Barac-Nieto, M; Liu, S M; Gupta, R K (1992) Na+ alters the affinity for glucose and phosphate in rat renal brush-border membranes: a study of NMR relaxation rates. Am J Physiol 263:C509-15

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