Mechanism of phosphaturia elicited by administration of phosphonoformate in vivo

Abstract

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.

MEPE has the properties of an osteoblastic phosphatonin and minhibin

“…Indeed, MEPE (ASARM peptide) may be one of a number of pathophysiological factors inhibiting phosphate transport and/or mineralization in Hyp. The acidic MEPE ASARM peptide is resistant to a vast array of proteases, is phosphorylated, with a low pI, high charge, low molecular weight and distinct physicochemical similarities to bisphosphonates (etidronate) and phosphonoformic acid [9,38,42,46,47,53,63,83,84,89,91,92]. Moreover, etidronate, phosphonoformic acid (PFA) and phosphonoacetic acid affect renal phosphate handling (direct binding), vitamin D metabolism and mineralization in vivo and in vitro [9,38,42,46,47,53,63,83,84,89,91,92].…”

“…The acidic MEPE ASARM peptide is resistant to a vast array of proteases, is phosphorylated, with a low pI, high charge, low molecular weight and distinct physicochemical similarities to bisphosphonates (etidronate) and phosphonoformic acid [9,38,42,46,47,53,63,83,84,89,91,92]. Moreover, etidronate, phosphonoformic acid (PFA) and phosphonoacetic acid affect renal phosphate handling (direct binding), vitamin D metabolism and mineralization in vivo and in vitro [9,38,42,46,47,53,63,83,84,89,91,92]. Thus, the ASARM peptide may also inhibit phosphate transport by directly binding to the phosphate transporter as demonstrated with PFA and etidronate [38,42,47,53,63,83,84,91,92] and in turn exacerbating the effects of other inappropriately processed phosphatonin(s) on NPT2 transcription (FGF-23?).…”

“…Moreover, etidronate, phosphonoformic acid (PFA) and phosphonoacetic acid affect renal phosphate handling (direct binding), vitamin D metabolism and mineralization in vivo and in vitro [9,38,42,46,47,53,63,83,84,89,91,92]. Thus, the ASARM peptide may also inhibit phosphate transport by directly binding to the phosphate transporter as demonstrated with PFA and etidronate [38,42,47,53,63,83,84,91,92] and in turn exacerbating the effects of other inappropriately processed phosphatonin(s) on NPT2 transcription (FGF-23?). Indeed, FGF23 and MEPE expression are closely correlated in Hyp [40].…”

Inhibition of Adenylyl and Guanylyl Cyclase Isoforms by the Antiviral Drug Foscarnet

“…The mechanism underlying the many additional side effects (in particular the neurological abnormalities) is unknown. Previous experiments rule out an effect of foscarnet on cAMP accumulation induced by parathyroid hormone in proximal renal tubules (7). In contrast, the mechanism by which foscarnet blocks the action of antidiuretic hormone is consistent with inhibition of cAMP formation (8).…”

“…The most common side effect of foscarnet is reversible nephrotoxicity. The phosphaturia associated with foscarnet treatment has been linked to a direct inhibition of Na ϩ /P i symport in the renal brush border (7). The mechanism underlying the many additional side effects (in particular the neurological abnormalities) is unknown.…”