We examined whether phosphonoformate (PFA) can cause phosphaturia through its direct action on brush-border membrane (BBM) in vivo. Infusion of PFA or of parathyroid hormone (PTH) to thyroparathyroidectomized rats caused a marked increase in fractional excretion of phosphate without changes in excretion of Na+ or of GFR. The PFA-induced phosphaturia was not accompanied by an increase in urinary adenosine-3',5'-cyclic monophosphate (cAMP); moreover, PFA added in vitro did not influence the PTH-sensitive adenylate cyclase and cAMP-phosphodiesterase in proximal convoluted tubules. In BBM vesicles (BBMV) from rats with PFA-elicited phosphaturia, neither the rate of Na+-Pi symport nor Na+-dependent binding of [14C]PFA on BBMV was changed, whereas in BBMV from PTH-infused rats the Vmax of Na+-Pi symport decreased. PFA is almost completely ultrafiltrable; no metabolic transformation of PFA was detected after [14C]PFA exposure to rat renal cortical slices, homogenate, or to blood. We conclude that PFA causes phosphaturia by direct inhibition of Na+-Pi symport across BBM in proximal tubules, acting from the luminal side. Thus PFA (foscarnet) has a unique direct mechanism of phosphaturic effect, via its action on Pi reabsorption in proximal tubules in vivo.

We tested the hypothesis that dopamine (DA) acts as an autocrine/paracrine regulator of Na(+)-Pi symport in proximal tubules, using opossum kidney (OK) cells as an in vivo model. Both DA and parathyroid hormone (PTH) increased adenosine 3',5'-cyclic monophosphate (cAMP) and inhibited Na(+)-gradient-dependent uptake of 32P but not that of L-[3H]-alanine. Incubation of OK cells with L-dopa, a DA precursor, resulted in accumulation of DA (7.4 nM), a ninefold increase of cAMP in the medium, and an inhibition (-10%) of Na(+)-Pi uptake. Carbidopa, an inhibitor of aromatic-L-amino acid decarboxylase, prevented the formation of DA from L-dopa, the increase in cAMP, and the inhibition of Na(+)-Pi cotransport. Pi-replete OK cells produced more DA (+15%) from L-dopa than Pi-deprived cells; however, the endogenous DA inhibited Na(+)-Pi cotransport both in Pi-deprived and in Pi-replete cells. Thus OK cells can synthesize DA from L-dopa in a quantity sufficient to elicit both the maximum DA-stimulated cAMP accumulation and inhibition of Na(+)-Pi cotransport in the same cell population. Our data, obtained on an in vitro system, support the hypothesis proposing that DA generated in proximal tubular cells can modulate, via cAMP, the Na(+)-Pi symport in the same or adjacent cells. If present in the kidney, this pathway might represent an autocrine/paracrine system that can contribute to regulation of renal Pi homeostasis.

The present study was performed to compare the effects of 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (cAMP analogue) and parathyroid hormone (PTH) infusion on segmental phosphate reabsorption in phosphate-deprived rats. Micropunctures of the late proximal and the early distal tubules were performed in acutely thyroparathyroidectomized (TPTX) rats fed either a normal (NPD) or low phosphate diet (LPD), and the phosphaturic response to infusion of PTH and cAMP analogue was evaluated. In NPD rats, PTH (n = 10) and the cAMP analogues (n = 11) markedly increased urinary phosphate excretion, due to inhibition of phosphate reabsorption along the proximal convoluted tubule and pars recta. In phosphate-deprived rats, PTH (n = 10) or the cAMP analogue (n = 11) did not increase urinary phosphate excretion. However, PTH and the cAMP analogue inhibited phosphate reabsorption along the proximal convoluted tubule but not in the pars recta in phosphate-deprived rats. We conclude that cAMP analogue infusion mimics the effect of PTH infusion on phosphate reabsorption along the proximal convoluted and proximal straight tubule in normal and phosphate-deprived rats. The resistance to the phosphaturic effect of PTH and cAMP infusions is a result of a blunted inhibition of phosphate reabsorption by the proximal convoluted tubule and also an increased phosphate reabsorption by the proximal straight tubule.

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