Substrates and inhibitors of phosphate transporters: from experimental tools to pathophysiological relevance.

The control of inorganic phosphate homeostasis is mediated through the activity of sodium-coupled Pi transporters located in the intestine, kidneys, and bone. To study these transporters in either the native tissue or after heterologous expression, it is very important to use specific inhibitors of the studied transporter, in order to know the corresponding relevance in the total Pi uptake and to differentiate from the activity of other transporters. Inhibitors are also necessary as drugs for treating Pi homeostasis disorders. Under normal physiological conditions, the renal and intestinal excretion of Pi matches dietary intestinal absorption, but when the number of non-functional nephrons increase in chronic kidney disease and end-stage renal disease, the excretion of surplus Pi is progressively impaired, thereby increasing the risk of hyperphosphatemia and Pi toxicity. When the compensatory mechanisms that increase Pi excretion fail, Pi toxicity can only be prevented by reducing the intestinal absorption of Pi through phosphate binders that reduced the free Pi concentration in the lumen, and inhibitors of intestinal Pi transporters and of the paracellular absorption route. Although many potentially interesting inhibitors have been reported to date, only a few are available for experimental purposes, and even fewer have been used in independent clinical trials. In this review, we summarize the different groups of compounds reported to date as inhibitors of Pi transport. To help understand and characterize the inhibition mechanisms, we also summarize the kinetic analysis approaches and screening methods that could be applied.

Inherited non-FGF23-mediated phosphaturic disorders: A kidney-centric review.

Phosphate is freely filtered by the glomerulus and reabsorbed exclusively in the proximal tubule by two key transporters, NaPiIIA and NaPiIIC, encoded by SLC34A1 and SLC34A3, respectively. Regulation of these transporters occurs primarily through the hormone FGF23 and, to a lesser degree, PTH. Consequently, inherited non-FGF23 mediated phosphaturic disorders are due to generalised proximal tubular dysfunction, loss-of-function variants in SLC34A1 or SLC34A3 or excess PTH signalling. The corresponding disorders are Renal Fanconi Syndrome, Infantile Hypercalcaemia type 2, Hereditary Hypophosphataemic Rickets with Hypercalciuria and Familial Hyperparathyroidism. Several inherited forms of Fanconi renotubular syndrome (FRTS) have also been described with the underlying genes encoding for GATM, EHHADH, HNF4A and NDUFAF6. Here, we will review their pathophysiology, clinical manifestations and the implications for treatment from a kidney-centric perspective, focussing on those disorders caused by dysfunction of renal phosphate transporters. Moreover, we will highlight specific genetic aspects, as the availability of large population genetic databases has raised doubts about some of the originally proposed gene-disease associations concerning phosphate transporters or their associated proteins.