Pharmacology of Mammalian Na+-Dependent Transporters of Inorganic Phosphate.

Inorganic phosphate (Pi) is an essential component of many biologically important molecules such as DNA, RNA, ATP, phospholipids, or apatite. It is required for intracellular phosphorylation signaling events and acts as pH buffer in intra- and extracellular compartments. Intestinal absorption, uptake into cells, and renal reabsorption depend on a set of different phosphate transporters from the SLC20 (PiT transporters) and SLC34 (NaPi transporters) gene families. The physiological relevance of these transporters is evident from rare monogenic disorders in humans affecting SLC20A2 (Fahr's disease, basal ganglia calcification), SLC34A1 (idiopathic infantile hypercalcemia), SLC34A2 (pulmonary alveolar microlithiasis), and SLC34A3 (hereditary hypophosphatemic rickets with hypercalciuria). SLC34 transporters are inhibited by millimolar concentrations of phosphonoformic acid or arsenate while SLC20 are relatively resistant to these compounds. More recently, a series of more specific and potent drugs have been developed to target SLC34A2 to reduce intestinal Pi absorption and to inhibit SLC34A1 and/or SLC34A3 to increase renal Pi excretion in patients with renal disease and incipient hyperphosphatemia. Also, SLC20 inhibitors have been developed with the same intention. Some of these substances are currently undergoing preclinical and clinical testing. Tenapanor, a non-absorbable Na+/H+-exchanger isoform 3 inhibitor, reduces intestinal Pi absorption likely by indirectly acting on the paracellular pathway for Pi and has been tested in several phase III trials for reducing Pi overload in patients with renal insufficiency and dialysis.

Type II Na+-phosphate Cotransporters and Phosphate Balance in Teleost Fish.

Teleost fish are excellent models to study the phylogeny of the slc34 gene family, Slc34-mediated phosphate (Pi) transport and how Slc34 transporters contribute Pi homeostasis. Fish need to accumulate Pi from the diet to sustain growth. Much alike in mammals, intestinal uptake in fish is partly a paracellular and partly a Slc34-mediated transcellular process. Acute regulation of Pi balance is achieved in the kidney via a combination of Slc34-mediated secretion and/or reabsorption. A great plasticity is observed in how various species perform and combine the different processes of secretion and reabsorption. A reason for this diversity is found in one or two whole genome duplication events followed by potential gene loss; consequently, teleosts exhibit distinctly different repertoires of Slc34 transporters. Moreover, due to habitats with vastly different salinity, teleosts face the challenge of either preserving water in a hyperosmotic environment (seawater) or excreting water in hypoosmotic freshwater. An additional challenge in understanding teleost Pi homeostasis are the genome duplication and retention events that diversified peptide hormones such as parathyroid hormone and stanniocalcin. Dietary Pi and non-coding RNAs also regulate the expression of piscine Slc34 transporters. The adaptive responses of teleost Slc34 transporters to e.g. Pi diets and vitamin D are informative in the context of comparative physiology, but also relevant in applied physiology and aquaculture. In fact, Pi is essential for teleost fish growth but it also exerts significant adverse consequences if over-supplied. Thus, investigating Slc34 transporters helps tuning the physiology of commercially valuable teleost fish in a confined environment.