The transport of solutes across the PT epithelium occurs via both transcellular and paracellular pathways. The transcellular pathway is generally a unidirectional, active process whereby substrates that are reabsorbed in the PT enter the epithelial cell across the apical membrane and subsequently are extruded across the basolateral membrane. The paracellular pathway in the PT is either a passive or secondarily active bidirectional process permitted by tight-junction proteins called claudins ¹¹ . Transport via the paracellular pathway is determined by the transepithelial electrochemical gradient and the permeability of the tight junction. About 65% of transepithelial sodium reabsorption in the nephron occurs in the PT, and two thirds of it occurs via the transcellular pathway in a process coupled to bicarbonate reclamation ^{12, 13} . As such, significant paracellular sodium reabsorption also takes place in this segment. Calcium reabsorption from the PT is primarily mediated by the paracellular pathway, while phosphate reabsorption occurs via the transcellular pathway ^{14, 15} . Both calcium and phosphate reabsorption in the PT are dependent to some degree on the transepithelial transport of sodium.

Electrolyte transport in the PT is regulated by multiple factors, including the calciophosphotropic hormones PTH and FGF23. These hormones interdependently regulate one another through the PTH-active vitamin D–FGF23 axes ( Figure 1) ¹⁶ . The regulatory mechanisms within these axes are complex and beyond the scope of this review. (The reader is referred to several recent reviews covering this topic ^{16– 19} .) Here, we focus on the effects of PTH, active vitamin D, and FGF23 on calcium and phosphate transport processes in the PT.

PTH is produced in the parathyroid gland and released when systemic calcium levels are reduced below the physiological set point. PTH increases serum calcium levels by directly increasing calcium resorption from bone and reabsorption from kidneys, while it indirectly stimulates intestinal absorption by increasing the synthesis of active vitamin D in the kidneys ^{20– 23} . Concomitantly, PTH inhibits phosphate reabsorption in the PT, thereby increasing phosphate excretion into urine ²⁴ . These actions on the PT are mediated by its direct interaction with the G protein–coupled type 1 PTH receptors (PTHRs) expressed on both apical and basolateral membranes ²⁵ . The major effects of PTH binding to the PTHR in the PT are mediated by protein kinase A (PKA) and protein kinase C (PKC). These protein kinases are stimulated by the G _s- and G _q/11-protein pathways, respectively ²⁶ . It is noteworthy that the apical PTHR preferentially signals through the PKC pathway ²⁵ . Ultimately, these signalling pathways modulate both the expression and membrane localization of transport proteins involved in the reabsorption of sodium, calcium, and phosphate across the PT epithelium.

PTH also increases plasma levels of active vitamin D via a direct effect on PT epithelial cells ¹⁷ . The enzyme responsible for hydroxylating 25-hydroxyvitamin D ₃ at the 1α-position, CYP27B1 or 1α-hydroxylase, is expressed in the PT and is upregulated by PTH ²⁷ . Though traditionally thought of as a calciotropic hormone, active vitamin D is a phospho- and calciotropic hormone that increases both serum calcium and phosphate levels by stimulating their intestinal absorption ²¹ . It also suppresses the release of PTH by downregulating PTH gene expression and increasing calcium-sensing receptor (CaSR) expression in the parathyroid gland ^{28, 29} . Even though active vitamin D directly increases the expression of proteins involved in calcium reabsorption in the distal nephron, it is unclear whether it exerts a direct effect on electrolyte handling in the PT which is independent of its secondary effects on other hormones.

FGF23 is a 251–amino acid peptide hormone synthesized and released from osteocytes and osteoblasts in response to elevations in systemic active vitamin D or phosphate or both ^{16, 19} . The primary action of FGF23 is to reduce PT phosphate reabsorption via binding to specific FGF receptors (FGFRs), including 1, 3, and 4, which are expressed on the basolateral membrane throughout the PT ^{30, 31} . Downstream signalling after FGFR activation reduces phosphate transporter expression and apical membrane localization in the PT. This signalling also depends on its cofactor, klotho, to activate the downstream signalling pathways. Though primarily thought of as a phosphotropic hormone, FGF23 is also a calciotropic hormone. With klotho as its cofactor, FGF23 directly modulates calcium reabsorption from the distal convoluted tubule (DCT) ^{32, 33} . Of note, PTH stimulates FGF23 release in rodents ^{29, 34, 35} , while in contrast to PTH, FGF23 indirectly suppresses the 1-hydroxylation of 25-dihydroxyvitamin D ₃ ¹⁷ . Thus, like PTH and active vitamin D, FGF23 regulates both calcium and phosphate homeostasis and therefore can be considered a calciophosphotropic hormone ^{6, 36} .

Calcium reabsorption in the PT is highly dependent on sodium transport. The kidneys filter more than 500 g of sodium and 180 L of water daily, while approximately 4 g of filtered sodium and 1–2 L of water is excreted in the urine ⁴⁹ . The PT reabsorbs about two thirds of the filtered sodium and water. Sodium reabsorption in the PT is primarily mediated by an active transcellular pathway ( Figure 2A) ⁵⁰ . Active reabsorption of sodium creates a small, albeit significant, osmotic gradient for water, which is reabsorbed trans- and paracellularly through the water-selective channel aquaporin-1 and tight-junction pore claudin-2, respectively ⁵¹ . The majority of sodium transport across the apical membrane occurs via the sodium proton exchanger isoform 3 (NHE3), encoded by the Slc9a3 gene, which is expressed along the PCT. Animals with a targeted deletion of Slc9a3 have a significant reduction in sodium and water reabsorption from the PT and display hypotension ^{13, 52– 54} . Though contributing minimally to sodium reabsorption from the PT, other apical membrane sodium-coupled cotransporters, including sodium-glucose, sodium-phosphate, and sodium–amino acid cotransporters, are expressed in this segment. These transporters account for less than 5% of total transcellular sodium reabsorption in the PT; thus, only those involved in phosphate transport will be discussed here.

Sodium is also reabsorbed from the PT through the paracellular pathway. The PT is very leaky, displaying a transepithelial resistance (TER) of 5–7 Ω·cm ^{2 11} . This leakiness is conferred by a tight-junction family of proteins called claudins. Claudin-2, -10a, and -17 are expressed in this nephron segment ^{11, 55, 56} . Claudin-2 forms a cation-selective, water-permeable pore, permitting paracellular diffusion of sodium, calcium, and water down their electrochemical gradients while restricting the diffusion of larger macromolecules ⁵⁷ . In the early PCT (S1), the transepithelial potential difference is lumen-negative, generated by the electrogenic sodium-glucose cotransporter (SGLT2) ⁵⁸ . Although this electrogenically favours paracellular cation secretion, this is overcome by the large amount of active sodium and consequent water reabsorption described above. The movement of water across the PT, when it occurs through the paracellular pore, can in turn carry other ions, including calcium, even against their respective transepithelial electrochemical gradient, in a process known as solvent drag ( Figure 2). This is supported by experiments using pharmacological blockade of NHE3 in a PT cell model and NHE3 knockout mice that display increased urinary calcium excretion and reduced calcium transport across intestinal epithelia ^{59– 61} . In contrast, the transepithelial potential difference across the late PT is lumen-positive, which is the result of reclamation of chloride ions and bicarbonate ⁵⁸ . This electrochemical gradient thus favours the reabsorption of sodium and calcium ⁵⁸ . As sodium and water are reabsorbed in the earlier portions of the PT, calcium in the tubular fluid becomes concentrated, generating a transepithelial chemical gradient that favours paracellular calcium reabsorption ^{37, 40, 41} . These mechanisms in concert generate a transepithelial electrochemical gradient from lumen-to-blood that drives calcium reabsorption. Taken together, the majority of PT calcium reabsorption occurs via a paracellular pathway.

PTH increases serum calcium in part by increasing the reabsorption of filtered calcium from the renal tubule, thereby reducing calcium excretion into urine. Paradoxically, micropuncture studies in the dog revealed that PTH reduces sodium, fluid, and calcium reabsorption from the PT, even though it still lowered urinary calcium excretion ^{43, 62} . This observation is reconciled by findings of enhanced calcium reabsorption in the later segments of the tubule following PTH administration ^{62– 64} . Microperfusion of rabbit cortical thick ascending limb (TAL) in the presence of PTH led to an almost fivefold increase in calcium flux across the segment with similar findings in mice ^{65, 66} . PTH also affects calcium reabsorption through a transcellular calcium transport pathway in the distal convolution, which relies on the calcium-permeable transient receptor potential V5 channel (TRPV5) ^{67– 69} . Consistent with this, PTH activates TRPV5 by increasing the open probability of the channel, membrane abundance, and total expression ^{68– 70} . A secondary effect of PTH on the DCT is to increase the amount of TRPV5 indirectly by increasing circulating active vitamin D levels, as this hormone also enhances calcium reclamation in the DCT ^{71, 72} .

A number of studies on animals demonstrate that the major effect of PTH on the PT is to inhibit sodium reabsorption, resulting in a natriuresis ( Figure 2B) ^{42, 43, 62, 73} . Various in vitro expression studies using opossum kidney (OK) cells found that acute and chronic incubation with PTH downregulates Slc9a3 at the transcriptional level, which is abolished by PKA inhibition (a downstream effector of PTH binding its receptor PTHR) ^{74– 76} . These studies also revealed that PTH decreases NHE3 membrane abundance ^{75, 77} . These cell culture studies are supported by in vivo work on PTH-infused rats that display significantly reduced renal NHE3 expression ^{78– 80} . Furthermore, microperfusion of rat PT after chronic PTH exposure found reduced transepithelial sodium transport along with increased sodium and water excretion ^{78, 79} . Thus, PTH directly inhibits NHE3-dependent transport. The actions of PTH on NHE3 are mediated by the phosphorylation of NHE3 at residue Ser605 by PKA ⁸¹ . Although PKC activation results in NHE3 inhibition, this effect is mediated through an unknown mechanism that does not appear to require direct NHE3 phosphorylation ⁸² . Both PKA and PKC are thought to interact with NHE3 through its PDZ domain–containing linker protein, the sodium-hydrogen exchanger regulatory factor 1 (NHERF-1); however, the precise mode of interaction is incompletely understood ^{83, 84} . Furthermore, the molecular details of PTH-mediated transcriptional regulation have not been fully elucidated ⁷⁴ .

PTH also inhibits sodium/potassium ATPase activity in the PT, which would secondarily inhibit the apical sodium-dependent cotransporter fundamental to transcellular sodium reabsorption ( Figure 2B). This occurs through the activation of PKC via a G _q/11 protein–coupled pathway after PTHR binding ^{85– 87} . Activated PKC translocates to the basolateral membrane and phosphorylates the alpha subunit of the sodium/potassium ATPase, inhibiting its activity ^{88, 89} . Given the abovementioned role of NHE3 and the sodium/potassium ATPase in paracellular calcium reabsorption, their inhibition by PTH would inhibit sodium reabsorption from the PT, which would decrease paracellular calcium reabsorption. This seems in direct contrast to the primary role of PTH to increase serum calcium levels. The reasons for this remain unclear. A previous attempt to reconcile this observation suggested that NHE3 inhibition alkalinizes the tubular fluid via reduced hydrogen secretion, thereby reducing reabsorption of bicarbonate ^{76, 78} . This hypothesis is supported by a micropuncture study, where acute administration of PTH increased distal delivery of bicarbonate, leading to an alkaline urine ⁹⁰ . Since TRPV5, which is expressed in the distal nephron, is activated by alkaline pH, this could increase distal transcellular calcium reabsorption through TRPV5 ^{76, 78, 91} . Micropuncture data further demonstrate the uncoupling of sodium and calcium transport in the distal nephron ^{42, 43, 62} . However, direct in vivo measurements of tubular pH after PTH administration and the consequent effect on calcium reabsorption in the distal tubule have not been made.

Alternatively, PTH-mediated inhibition of PT sodium reabsorption might affect urinary calcium excretion by altering the glomerular filtration rate (GFR). Multiple in vivo studies found that exogenous PTH administration decreases GFR ^{92– 94} . Consistent with this, patients with primary hyperparathyroidism show significantly reduced GFR ⁹⁵ . An explanation for this observation is that PTH stimulates tubuloglomerular feedback by increasing the distal delivery of chloride. The majority of chloride reclamation from the PT occurs through the paracellular pathway, driven by the transepithelial electrochemical gradient ⁹⁶ . PTH-mediated inhibition of sodium reabsorption in the early PT would result in a more positive lumen, which in turn would favour retention of chloride and result in increased distal delivery of chloride. This would stimulate tubuloglomerular feedback, thereby decreasing GFR ⁹⁷ . The PTH effect on GFR would not directly affect PT calcium transport. However, it would reduce the filtered calcium load and the amount of calcium in the ultrafiltrate. This would decrease the amount of calcium needed to be reabsorbed by active calcium transport in the distal nephron, thereby maximizing calcium reabsorption. Further studies are required to confirm this hypothesis.

The effect of calciophosphotropic hormones on ion transport in the cortical TAL ^{98– 100} and the distal convolution ^{67– 69, 71, 101} have been studied. However, there is a paucity of recent studies looking at the PT. In particular, the potential regulation of tight-junction permeability by calciophosphotropic hormones, including PTH, has received little attention. Functional data suggest a relationship between PTH signalling and altered paracellular transport in the PT ¹⁰² . PTH administration to rats acutely decreased paracellular solute reabsorption from the PT ¹⁰² . This is further supported by a microperfusion study that showed reduced water-driven paracellular solute transport (that is, reduced solvent drag) across rabbit PCTs after infusion of cyclic AMP (a downstream second messenger of PTH-PTHR activation) ¹⁰³ . Consistent with the abovementioned studies, inhibition of NHE3 in an intestinal cell culture model resulted in increased TER consistent with reduced tight-junction permeability ¹⁰⁴ as TER across a leaky epithelium is predominantly a reflection of paracellular ion permeability. Together, these studies suggest that PTH inhibits paracellular transport in the PT by decreasing tight-junction permeability, which likely also affects the permeation of calcium, although this has not been specifically tested. We are unaware of attempts to delineate the molecular components involved in regulation of paracellular permeability following PTH application. Further research is required to do so and to assess the effect of PTH on the transcellular calcium absorption pathway in the late PT.

FGF23 also affects PT solute transport by acting on sodium-phosphate cotransporters. However, given the relatively small amount of sodium reabsorbed via this pathway, this primarily decreases phosphate rather than sodium transport and therefore is discussed below. Currently, we are unaware of data demonstrating an effect of FGF23 on transcellular sodium transport or tight-junction permeability in the PT. It should be kept in mind, however, that FGF23 participates in calcium homeostasis through the enhancement of active vitamin D inactivation as well as by enhancing distal tubular calcium reabsorption through TRPV5 ³⁴ .

There is evidence of calcium sensing by the PT. The CaSR detects elevated serum calcium. It signals through a G _q/11 protein–coupled pathway inhibiting PTH release from the parathyroid gland and decreases calcium reabsorption from the TAL ^{105, 106} . Several studies have reported CaSR expression in the brush border membrane of PT epithelial cells ^{107, 108} , but another study contradicts this observation ¹⁰⁰ . A recent study using both monoclonal and polyclonal antibodies against the CaSR found a low level of expression in PT ¹⁰⁹ . Regardless, a functional study using conditionally immortalized PT epithelial cells isolated from the urine of healthy subjects revealed activation of the G _q/11 pathway with exposure to increased extracellular calcium as well as its allosteric agonist NPS-R568 ¹¹⁰ . The physiological role of a CaSR in the PT appears to be to antagonize the inhibitory effects of PTH in PT transport processes. In microperfused late PT (S3 region) and OK cells, the addition of the CaSR agonists gadolinium and NPS R467 abolishes the phosphaturic effects of PTH ¹⁰⁸ . Further microperfusion and micropuncture experiments on rat PT demonstrate a link between CaSR activation and NHE3. Increased fluid absorption and intracellular pH were seen in response to high luminal calcium or NPS-R568, an effect that was absent in CaSR knockout animals ¹¹¹ . Together, these studies support the presence of a functional calcium-sensing mechanism in the PT, which antagonizes PTHR activation.

Global PT dysfunction results in glycosuria, aminoaciduria, low-molecular-weight proteinuria and renal tubular acidosis. This constellation of symptoms is called the Fanconi syndrome. Perhaps not surprisingly, the Fanconi syndrome often includes alteration in vitamin D metabolism ¹¹² . Dent’s disease and the oculo-renal syndrome of Lowe’s disease are typically accompanied by hypercalciuria and nephrocalcinosis ^{113, 114} . These diseases are the result of mutations in CLCN5 or OCRL1 ^{115, 116} . The former gene encodes a transmembrane proton-chloride exchanger (also present intracellularly), and the latter a lipid phosphatase involved in the shuttling of lipid between endomembrane compartments ^{117, 118} . Why these gene defects result in a PT calcium phenotype is unknown and is an area of research that requires exploring. Given the possible involvement of CLCN5 in luminal chloride and proton balance, it is possible that loss-of-function mutation in the CLCN5 gene alters the transepithelial electrical gradient in the PT, thus perturbing various solute transport processes ¹¹⁷ . However, further studies employing cell and animal models of CLCN5 and OCRL1 mutations will help delineate the pathophysiological mechanism of these syndromes.

Phosphate is vital to bone mineralization, maintaining cellular energy stores, and to cell signalling. The kidneys are essential to maintaining systemic phosphate levels, as the majority of ingested phosphate is absorbed from the intestine. Less than 1% of the body’s phosphorus exists in a solubilized form as either dihydrogen phosphate (H ₂PO ₄ ¹⁻) or mono-hydrogen phosphate (HPO ₄ ²⁻), and the pH determines the fraction of each. The remaining fractions are stored either as part of hydroxyapatite in bone (~85%) or intracellularly (~15%) ¹¹⁹ . In adults, the kidneys filter approximately 200 mmoles of phosphate daily, and about 90% of it is reabsorbed back into the bloodstream. Of this filtered fraction, 90% is reabsorbed from the PT.

In the PT, phosphate reabsorption occurs primarily via a transcellular pathway ( Figure 3). Paracellular phosphate reabsorption from this tubule segment has been described as insignificant in comparison with transcellular reabsorption ^{4, 5, 120, 121} . Sodium-coupled phosphate cotransporters NaPi-IIa, NaPi-IIc, and PiT-2 mediate the cellular entry of filtered phosphate ions from the lumen ⁵ . Apical phosphate entry is facilitated by secondary active transport of sodium, the electrochemical gradient of which is maintained by the basolateral sodium/potassium ATPase. The transport capacity of the PT for phosphate is determined primarily by the abundance of sodium-coupled phosphate transporters, which is due to the steep electrical gradient across the apical membrane (about −70 mV) and a low cytosolic sodium concentration. Expression studies in rodent PT reveal that NaPi-IIa expression is high in the early PT and decreases along the length of this nephron segment, but the fact that NaPi-IIc and PiT-2 are expressed throughout the PT highlights the importance of the early PT to phosphate reabsorption ^{122, 123} . The NaPi-II transporter family shows preference for divalent phosphate (HPO ₄ ²⁻). NaPi-IIa is electrogenic (couples 3 Na ⁺ to 1 phosphate), and NaPi-IIc is electroneutral (couples 2 Na ⁺ to 1 phosphate) ^{124– 126} . In contrast, PiT-2 has greater affinity for monovalent phosphate ions (H ₂PO ₄ ⁻) and is electrogenic ^{127, 128} . Genetic knockout studies in mice demonstrate that NaPi-IIa constitutes about 70% of phosphate reabsorption in the PT in this species ^{129– 131} . Loss-of-function mutations in the NaPi-IIa cotransporter ( SLC34A1) in humans, in contrast to rodents, causes renal calcification and generalized proximal-tubular dysfunction (that is, the Fanconi syndrome) rather than specific phosphate disturbances ^{132, 133} . Moreover, NaPi-IIc in the human kidney likely contributes substantially to phosphate reabsorption, as patients with hereditary hypophosphatemic rickets with hypercalciuria—genetic mutations in the NaPi-IIc ( SLC34A3 gene)—show renal wasting of phosphate due to impaired NaPi-IIc function ^{134, 135} . After apical entry, subsequent intracellular diffusion and basolateral extrusion of phosphate complete reabsorption across PT epithelia ¹²² . Although little is known about the basolateral extrusion mechanism, a recent nephron-specific knockout of the xenotropic and polytropic retroviral receptor gene ( Xpr1) in mice resulted in hypophosphatemia and hyperphosphaturia, suggesting a role for this transporter in renal tubular phosphate reabsorption ¹³⁶ . The protein product of Xpr1 also shares a sequence homology similar to that of a phosphate extrusion transporter in plants (PHO1). Additional experiments need to be carried out to confirm its role in transcellular phosphate reabsorption.

PTH and FGF23 regulate phosphate reabsorption in the PT, which in turn regulates plasma phosphate levels. Active vitamin D increases serum phosphate via enhanced intestinal absorption and potentially via increased PT reabsorption ^{137, 138} . However, limited direct evidence of the effect on the PT and confounding effects of PTH and FGF23 complicates this interpretation ¹ . PTH attenuates renal phosphate reabsorption by reducing the membrane abundance of NaPi-IIa, NaPi-IIc, and PiT-2 cotransporters ( Figure 3) ^{139– 141} . PTH acutely decreases the abundance of apical NaPi-IIa cotransporters by stimulating endocytosis and ultimately their degradation ^{142, 143} . PTH induces NaPi-IIa endocytosis through a complex intracellular pathway, which has been reviewed previously ^{4, 5} . In short, the PTH-PTH1R interaction results in phosphorylation of PDZ domain–containing proteins—including NHERF-1—via activation of PKA and PKC, the signalling pathways that inhibit NHE3. NHERF-1 anchors NaPi-IIa to the cytoskeleton and its phosphorylation releases the transporter, permitting endocytosis and degradation in response to PTH ^{144– 147} . Patients with mutations in NHERF-1 ( SLC9A3R1) display phosphaturia and nephrolithiasis but have otherwise normal PT function ^{148, 149} . Interestingly, the mutations are not in the PDZ domain. Instead, these NHERF-1 mutants when expressed in vitro confer enhanced PTH-induced cAMP generation and inhibit phosphate transport, suggesting that NHERF-1 is a key component in PTH-mediated phosphaturic effects ¹⁴⁹ . PTH is also implicated in the internalization of NaPi-IIc; however, it is not subsequently degraded ^{140, 141} . The molecular pathway whereby NaPi-IIc is downregulated is currently unknown. Nevertheless, like its effect on calcium handling, PTH decreases phosphate reabsorption in the PT. However, unlike calcium, where the distal tubule compensates for calcium loss in PT, the distal nephron has limited ability to reabsorb phosphate. Consequently, elevated PTH induces hyperphosphaturia and hypophosphatemia—symptoms commonly observed in patients with primary hyperparathyroidism ¹⁵⁰ .

Osteocytes and osteoblasts produce FGF23 in response to an increase in plasma phosphate levels and in response to active vitamin D ( Figure 1). FGF23 decreases serum phosphate levels, primarily by reducing phosphate reabsorption from the PT and by reducing intestinal phosphate reabsorption through the inactivation of active vitamin D. In the kidney, FGF23 stimulates the internalization and subsequent degradation of NaPi-IIa and NaPi-IIc cotransporters by phosphorylation of NHERF-1 in a process similar to PTH ( Figure 3B) ^{33, 151, 152} . This occurs through mitogen-activated protein kinase (MAPK) and serum/glucocorticoid-regulated kinase-1 (SGK-1) signalling pathways that are activated by FGFR 1, 3, and 4 ^{153– 157} . Unlike PTH, the FGF23-FGFR signalling pathway also downregulates transcription and translation of NaPi-IIa and NaPi-IIc cotransporters, contributing to a decrease in abundance of proteins in the PT ^{33, 158, 159} . Moreover, PTH-induced endocytosis of NaPi-IIa is abolished by inhibition of the MAPK pathway, suggesting a functional crosstalk mechanism between PTH and FGF23 signalling pathways in the PT ¹⁶⁰ . Thus, the physiological actions of PTH on phosphate excretion and consequent reductions in serum phosphate level are complemented by the action of FGF23.

Direct phosphate sensing is another mechanism by which phosphate transport may be regulated in the PT. A phosphate-sensing mechanism has been observed in cell culture where increased extracellular phosphate activates the MAPK pathway ¹⁶¹ . This has also been observed in other cell lines, including human embryonic kidney 293 cells ^{154, 162} where increased extracellular phosphate activates the MAPK pathway that FGF23 stimulates, without altering expression of FGF, FGFR, or klotho ¹⁵⁴ . This finding is not surprising when we consider the functional role of FGF23. As a phosphaturic hormone, FGF23 is released in response to high serum phosphate levels. Consequently, FGF23 signals the PT to attenuate the reabsorption of phosphate through NaPi-II cotransporters, inducing phosphate excretion. Therefore, it is likely that increased extracellular phosphate stimulates the same signalling pathway activated by FGF23. However, work remains to confirm this, including exploring the effects of high extracellular phosphate on MAPK signalling in vivo, as well as whether phosphate directly regulates gene expression, trafficking, or activity (or a combination of these) of known phosphate transporters in PT.