Proximal Tubular Phosphate Reabsorption: Molecular Mechanisms

Abstract

Renal proximal tubular reabsorption of P(i) is a key element in overall P(i) homeostasis, and it involves a secondary active P(i) transport mechanism. Among the molecularly identified sodium-phosphate (Na/P(i)) cotransport systems a brush-border membrane type IIa Na-P(i) cotransporter is the key player in proximal tubular P(i) reabsorption. Physiological and pathophysiological alterations in renal P(i) reabsorption are related to altered brush-border membrane expression/content of the type IIa Na-P(i) cotransporter. Complex membrane retrieval/insertion mechanisms are involved in modulating transporter content in the brush-border membrane. In a tissue culture model (OK cells) expressing intrinsically the type IIa Na-P(i) cotransporter, the cellular cascades involved in "physiological/pathophysiological" control of P(i) reabsorption have been explored. As this cell model offers a "proximal tubular" environment, it is useful for characterization (in heterologous expression studies) of the cellular/molecular requirements for transport regulation. Finally, the oocyte expression system has permitted a thorough characterization of the transport characteristics and of structure/function relationships. Thus the cloning of the type IIa Na-P(i )cotransporter (in 1993) provided the tools to study renal brush-border membrane Na-P(i) cotransport function/regulation at the cellular/molecular level as well as at the organ level and led to an understanding of cellular mechanisms involved in control of proximal tubular P(i) handling and, thus, of overall P(i) homeostasis.

Intestinal and renal adaptation to a low-Pi diet of type II NaPi cotransporters in vitamin D receptor- and 1αOHase-deficient mice

“…Because renal excretion of P i is determined largely by the abundance of the type IIa NaP i cotransporter in the apical membranes of proximal tubular cells (19), the total abundance of NaP i -IIa contained in a crude membrane fraction of renal cortex tissue was analyzed using immunoblotting (Fig. 2).…”

“…In the kidney, the role of 1,25(OH) 2 D in P i reabsorption, and more specifically its effect on the abundance of NaP i -IIa cotransporter in proximal tubules, is less clear. Conflicting results have been reported indicating that a possible action of 1,25(OH) 2 D on the NaP i -IIa cotransporter is dose dependent and depends on alterations in the level of PTH (8,19). As demonstrated recently, a genomic effect of low-P i diet on the upregulation of NaP i -IIa seems unlikely, because in cortical as well as juxtamedullary proximal tubular S1 and S3 segments of adult mice, the abundance of NaP i -IIa mRNA was not altered by a low-P i diet (17).…”

“…In adult mice, renal reabsorption of P i is determined largely by the abundance of NaP i type IIa (NaP i -IIa) in the brush-border membrane vesicles (BBMV) of proximal tubular cells and in small intestine by NaP i type IIb (NaP i -IIb), the only apical NaP i cotransporter known to be involved in the absorption of P i (14,19). Thus regulation of intestinal absorption and renal reabsorption of P i is mainly explained by alterations in the apical abundances of NaP i -IIb and NaP i -IIa, respectively (12,15,19,28). Low dietary intake of P i is a well-known stimulator of both renal and small intestinal P i handling (3,6,16).…”

New Insights Into the Pathogenesis of Idiopathic Hypercalciuria

“…Regulated renal calcium transport involves a calcium channel, TRPV5, found in the distal nephron; it is closely related to the analogous channel, TRPV6, found in the gut [13]. Proximal tubule phosphate transport is primarily conducted by a sodium-phosphate cotransporter, NPT-2a, a member of the type 2 family of phosphate transport proteins [55]. Both of these transporters are controlled by the PTH -vitamin D axis, but in the last few years, new transport regulators have been identified.…”

Vascular Calcification

“…Types I and II are most common in the kidney and intestine. Type III is expressed throughout the body (29). PCR and Northern blot analysis have identified the NPC in HSMC as Pit-1 (Glvr-1), which is a type III NPC.…”