Mechanisms of phosphate transport

Abstract

Over the past 25 years, successive cloning of SLC34A1, SLC34A2 and SLC34A3, which encode the sodium-dependent inorganic phosphate (P i ) cotransport proteins 2a-2c, has facilitated the identification of molecular mechanisms that underlie the regulation of renal and intestinal P i transport. P i and various hormones, including parathyroid hormone and phosphatonins, such as fibroblast growth factor 23, regulate the activity of these P i transporters through transcriptional, translational and post-translational mechanisms involving interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking of the transporters via endocytosis and exocytosis. In humans and rodents, mutations in any of the three transporters lead to dysregulation of epithelial P i transport with effects on serum P i levels and can cause cardiovascular and musculoskeletal damage, illustrating the importance of these transporters in the maintenance of local and systemic P i homeostasis. Functional and structural studies have provided insights into the mechanism by which these proteins transport P i , whereas in vivo and ex vivo cell culture studies have identified several small molecules that can modify their transport function. These small molecules represent potential new drugs to help maintain P i homeostasis in patients with chronic kidney disease -a condition that is associated with hyperphosphataemia and severe cardiovascular and skeletal consequences.

Welche Rolle spielen Phosphathaushalt und Gefäßverkalkungen bei der chronischen Niereninsuffizienz?

“…In der Nahrung künstlich zugesetzte Phosphate sind wahrscheinlich viel besser resorbierbar als in pflanzlicher Nahrung vorhandene Phosphate. Die Phosphatspiegel im Blut zeigen eine deutliche zirkadiane Rhythmik und sind vormittags gering, aber nachts hoch [1][2][3].…”

Role of sodium‐dependent Pi transporter/Npt2c on Pi homeostasis in klotho knockout mice different properties between juvenile and adult stages

“…Sodium‐dependent phosphate transporters (the solute carrier 34 [SLC34] family) have an important role in regulating serum Pi levels. SLC34A1/NPT2A/NaPi‐2a and SLC34A3/NPT2C/NaPi‐2c are predominantly expressed in the proximal tubules of the kidney (Kaneko et al, ; Lederer & Miyamoto, ; Levi et al, ). The phenotypic differences resulting from NPT2A and NPT2C gene mutations may be due to differential dominance of the transporters involved in Pi homeostasis.…”

“…Furthermore, only Npt2a/Npt2c double knockout (KO) mice exhibit a physiology similar to that of patients with HHRH (Segawa, Onitsuka, Furutani, et al, ). In rodents, Npt2a is a major functional NaPi cotransporter in the proximal tubules (Kaneko et al, ; Lederer & Miyamoto, ; Levi et al, ). Npt2c is important for Pi reabsorption in weanling animals but mediates a very small percentage of Pi reabsorption in adult animals (Segawa et al, ).…”

“…predominantly expressed in the proximal tubules of the kidney (Kaneko et al, 2011;Lederer & Miyamoto, 2012;Levi et al, 2019). The phenotypic differences resulting from NPT2A and NPT2C gene mutations may be due to differential dominance of the transporters involved in Pi homeostasis.…”

Clinical and laboratory features associated with serum phosphate concentrations in malaria and other febrile illnesses

“…Only about 1% of body phosphorous content is contained in the plasma, but this phosphate is important because it is the medium of exchange between different body compartments, particularly when phosphate is required rapidly [9,13,14]. Phosphate homeostasis is maintained by the action of parathyroid hormone (PTH), calcitriol, and increasingly well-characterized phosphatonin peptides, which regulate uptake from the intestine, reabsorption by the kidney, and phosphate exchange between bone and extracellular pools [9,[13][14][15]. Phosphate is co-transported with sodium by multiple tissue-specific phosphate transporters, and this transport is influenced by potassium and acid-base status [15].…”