Recent findings in phosphate homeostasis Dominique Prie ´ a,b , Laurent Beck a , Pablo Urena a,b,c and Ge ´rard Friedlander a,b,d Purpose of review We summarize the most recent findings on the proteins that interact with sodium/inorganic phosphate (Na/Pi) cotransporters, the factors that regulate Pi homeostasis and their role in pathology. Recent findings Studies in animal models and cell lines identified proteins mandatory to correct trafficking of the kidney-specific Na/Pi cotransporter NPT2a and its control by the parathyroid hormone. Expression of the intestinal cotransporter NPT2b is controlled by calcitriol, the ubiquitin ligase Nedd-4 and the serum glucocorticoid inducible kinase. Recent data confirm that fibroblast growth factor 23 plays a central role in the control of Pi homeostasis. Mice disrupted for or overexpressing this gene exhibit significant alteration of Pi transport and calcitriol metabolism. In humans, fibroblast growth factor 23 mutations are responsible for autosomal hypophosphataemic rickets or tumoral calcinosis. This gene also seems to be involved in hyperparathyroidism in patients with chronic kidney disease. Several new phosphaturic factors have been identified. Moderate increases in serum Pi concentration may have deleterious effects on lifespan in humans with chronic kidney disease. Disruption of the Klotho gene in mice is associated with hyperphosphataemia and decreased lifespan. Polymorphisms in this gene, in humans and in mice, influence vascular calcification and survival. Summary Pi homeostasis depends on the activity of Na/Pi cotransporters in intestine and kidney. Na/Pi transporter activity is regulated by cellular and endocrine factors, among which fibroblast growth factor 23 plays a central role. Adequate control of Pi homeostasis is crucial, as a moderate increase in serum Pi concentration and polymorphisms in genes involved in Pi metabolism may influence the aging process and lifespan. Keywords calcitriol, fibroblast growth factor 23, intestine, kidney, lifespan, phosphate Curr Opin Nephrol Hypertens 14:318–324. ß 2005 Lippincott Williams & Wilkins. a Inserm U 426 et Institut Fe ´ de ´ ratif de Recherche 02, Faculty of Medicine, Xavier Bichat, Paris, France, b Department of Physiology and Clinical Investigation, Ho ˆ pital Necker-Enfants Malades, Assistance Publique-Ho ˆ pitaux de Paris, Paris, France, c Department of Nephrology and Dialysis, Clinique de l’Orangerie, Aubervilliers, France and d Department of Physiology and Clinical Investigation, Ho ˆ pital Europe ´en Georges Pompidou, Paris, France Correspondence to Dominique Prie ´ MD PhD, Service de Physiologie-Explorations Fonctionnelles, Ho ˆ pital Necker-Enfants Malades, Assistance Publique-Ho ˆ pitaux de Paris, 149 rue de Se ` vres, 75015 Paris, France Tel: +33 1 44 381962; fax: +33 1 44 49 40 39; e-mail: prie@necker.fr Current Opinion in Nephrology and Hypertension 2005, 14:318–324 Abbreviations ADHR autosomal dominant hypophosphataemic rickets BBM brush border membrane FGF-23 fibroblast growth factor 23 MEPE matrix extracellular phosphoglycoprotein NHERF1 sodium–proton exchanger regulatory factor 1 PTH parathyroid hormone sFRP4 secreted frizzled-related protein 4 XLH X-linked hypophosphataemia ß 2005 Lippincott Williams & Wilkins 1062-4821 Introduction Inorganic phosphate (Pi) plays a critical role in bone mineralization and various cellular functions. Pi homeo- stasis depends on Pi uptake in the small intestine and Pi reabsorption in the renal proximal tubule. Pi enters the cells via Na/Pi cotransporters, the activity of which is regulated by hormones. In this review we will summarize recent findings on the following: (1) proteins that interact with the Na/Pi cotransporters to form functional molecular complexes in cells; (2) identification of new peptides that modify Na/Pi cotransporter activity; and (3) the emerging possibility that Pi may have deleterious effects on survival and aging in individuals with normal renal function. Phosphate transporters Three types of Na/Pi cotransporters have been described so far based on the structural similarity deduced from their amino acid sequences. These families differ by their affinity for Pi, their distribution in the body and the mechanisms that control their activity. The type 1 Na/ Pi family is represented by three members: NPT1, NPT3, NPT4. These transporters are expressed at the plasma or at the microsomal membranes of the cells in the kidney, the intestine and the liver. Although they display Pi uptake capacity, they may also transport other anions, and their physiological roles remain to be established. Modifications of expression or mutations of NPT1 and NPT4 have been reported in various disorders [1,2]. The type 3 Na/Pi transporter family is composed of Pit1 and Pit2. These proteins were initially identified as virus receptors but they transport phosphate into cells with a high affinity. They are widely expressed in tissues, 318