Physiological regulation of phosphate by vitamin D, parathyroid hormone (PTH) and phosphate (Pi)

Abstract

Inorganic phosphate (Pi) is an abundant element in the body and is essential for a wide variety of key biological processes. It plays an essential role in cellular energy metabolism and cell signalling, e.g. adenosine and guanosine triphosphates (ATP, GTP), and in the composition of phospholipid membranes and bone, and is an integral part of DNA and RNA. It is an important buffer in blood and urine and contributes to normal acid-base balance. Given its widespread role in almost every molecular and cellular function, changes in serum Pi levels and balance can have important and untoward effects. Pi homoeostasis is maintained by a counterbalance between dietary Pi absorption by the gut, mobilisation from bone and renal excretion. Approximately 85% of total body Pi is present in bone and only 1% is present as free Pi in extracellular fluids. In humans, extracellular concentrations of inorganic Pi vary between 0.8 and 1.2 mM, and in plasma or serum Pi exists in both its monovalent and divalent forms (H2PO4− and HPO42−). In the intestine, approximately 30% of Pi absorption is vitamin D regulated and dependent. To help maintain Pi balance, reabsorption of filtered Pi along the renal proximal tubule (PT) is via the NaPi-IIa and NaPi-IIc Na+-coupled Pi cotransporters, with a smaller contribution from the PiT-2 transporters. Endocrine factors, including, vitamin D and parathyroid hormone (PTH), as well as newer factors such as fibroblast growth factor (FGF)-23 and its coreceptor α-klotho, are intimately involved in the control of Pi homeostasis. A tight regulation of Pi is critical, since hyperphosphataemia is associated with increased cardiovascular morbidity in chronic kidney disease (CKD) and hypophosphataemia with rickets and growth retardation. This short review considers the control of Pi balance by vitamin D, PTH and Pi itself, with an emphasis on the insights gained from human genetic disorders and genetically modified mouse models.

Inflammation and Premature Ageing in Chronic Kidney Disease

“…In hypophosphatemia, either normal or increased levels of the active metabolite 1,25(OH) 2 vitamin D 3 are observed in humans [66], and 1,25(OH) 2 vitamin D 3 increases the rate of intestinal P i resorption [67]. Furthermore, the parathyroid glands are affected by elevated serum P i levels and release PTH, which enhances urinary P i excretion by PTH-induced removal of the renal sodium P i cotransporters from the apical membrane [68]. Bone-derived FGF-23 limits hyperphosphatemia by inducing phosphaturia and suppressing vitamin D secretion [69].…”

Clinical aspects of the phosphate transporters NaPi-IIa and NaPi-IIb: mutations and disease associations

“…Other than age, NaPi-IIa expression is regulated primarily by dietary phosphate intake and the hormones parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) [41]. Low dietary phosphate or malabsorption syndromes resulting in poor phosphate gastrointestinal uptake increase NaPi-IIa expression while high dietary phosphate downregulates NaPi-IIa expression [5].…”

The kinetics of inorganic phosphate excretion in the acidotic rabbit during intravenous phosphate loading: a pseudo-ruminant model

“…Two main families of phosphate transporters facilitate the renal reabsorption of phosphate. These include the SLC34 family (NaPi-IIa & NaPi-IIc) and the SLC20 family (PiT-1& PiT-2), respectively 7,8 .…”

“…These include parathyroid hormone (PTH), calcitriol, and a number of phosphatonins, of which fibroblast growth factor-23 and α-klotho have been the best characterized. Klotho acts as a co-factor that is mandatory for FGF23 action 7,8 .…”