The kidney plays a major role in the maintenance of inorganic phosphate (P i ) homeostasis and, as such, ensures that an adequate supply of this ubiquitous anion is available for proper cellular function and skeletal mineralization. Physiologic studies have revealed that the bulk of filtered P i is reabsorbed in the proximal tubule, with higher rates of reabsorption in the early segments and in deep nephrons. This review will summarize the progress that has been made in the molecular identification and regulation of renal P i transporters. In addition, it will focus on the pathophysiology of inherited (X-linked hypophosphatemia [XLH], autosomal dominant hypophosphatemic rickets [ADHR], and hereditary hypophosphatemic rickets with hypercalciuria [HHRH]) and acquired (oncogenic hypophosphatemic osteomalacia [OHO]) renal P i wasting disorders, and discuss the role of two novel P i -regulating genes, PHEX and FGF-23, in the regulation of P i homeostasis. For recent reviews see references 1-5.
Cellular Mechanism of Proximal Tubular P i ReabsorptionP i reabsorption in the proximal tubule is mediated by Na ϩ -dependent, secondary-active transport mechanisms. Influx of P i from the tubular lumen into the epithelial cell involves brush border membrane-associated Na/P i cotransporter(s) which are rate-limiting and targets for physiologic/pathophysiologic regulation. Efflux of P i across the basolateral membrane may involve an anion exchange mechanism and/or a "P i leak" to complete transcellular reabsorptive flux, and a Na ϩ -dependent P i uptake mechanism to guarantee P i uptake from the interstitium if apical influx is insufficient to maintain cellular metabolism [for review see (1)].