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Phosphate transport: from microperfusion to molecular cloning

  • Heini Murer
  • Jürg BiberEmail author
  • Ian C. Forster
  • Andreas Werner
Editorial
  • 263 Downloads

Inorganic phosphate (Pi) is a constituent of important biological molecules (e.g., nucleic acids and phospholipids) and is essential for cellular energetics and signaling, and protein synthesis as well as skeletal development in all mammalian organisms. Inadequate Pi supply causes bone malformations such as rickets and spinal deformations, whereas an excess in Pi is linked to vascular calcification or ectopic CaPi deposits. In general, whole-body Pi homeostasis is maintained by transepithelial transport mechanisms in the small intestine and kidney where Pi is absorbed from the diet and reabsorbed from the glomerular filtrate, respectively. The renal proximal tubule is the main locus of Pi regulation so that under “steady-state” physiological conditions, renal Pi-excretion corresponds approximately to dietary Pi intake.

Membrane transport proteins belonging to the SLC34 solute carrier family1 lie at the heart of maintaining Pi homeostasis. In the small intestine, NaPi-IIb (SLC34A2) mediates luminal Pi uptake together with a paracellular component, whereas the renal isoforms NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) are responsible for Pi reabsorption in the proximal tubule. This Special Issue focusing on phosphate transport mediated by SLC34 proteins was conceived to coincide with an important milestone in renal physiology: the expression cloning of the first member of the SLC34 family (NaPi-IIa) just over a quarter of a century ago [33]. This, together with the subsequent identification of the other two SLC34 isoforms [24, 42], has paved the way for a deeper understanding of the molecular basis of Pi homeostasis, many aspects of which are the subject of dedicated reviews in this issue. Whereas the pivotal role of SLC34 cotransporters in maintaining Pi homeostasis is undisputed, other carriers such as PIT-1 and PIT-2 (SLC20 family) may also contribute to epithelial transport of Pi in the intestine and the kidney. However, their respective contributions to overall Pi balance remain to be clarified and will not be the main focus of the present Special Issue.

Following the cloning of NaPi-IIa [33], the phosphate physiology field has progressed rapidly, benefitting from advances in molecular and cell biology, imaging, and biophysical assays, as exemplified by the invited articles. Therefore, it is easy to overlook how key aspects of our present knowledge of Pi handling had already been established prior to 1993. A brief reflection on the main findings of these earlier studies seems appropriate to set the scene for the developments that have taken place over the past 25 years.

Indeed, in the three decades that preceded the NaPi-IIa cloning, ground-breaking studies using ex vivo and in vivo preparations revealed fundamental properties of Pi transport physiology that are still valid today, including the location of active sites of absorption and reabsorption, the energetic basis of the transport mechanism, and the identification of some of the key physiological regulators. One of the first attempts to identify the site of renal Pi reabsorption involved micropuncture of intact kidneys to compare samples of fluid from the renal tubules in normal and Pi-loaded rats [45]. It was shown that the reabsorption of filtered Pi occurs primarily in the proximal tubules and furthermore, it was concluded that this process probably involves an active transport process [45]. Later, using the standing droplet method and simultaneous microperfusion of the peritubular capillaries performed in situ on superficial renal tubules (e.g., [40]) (Fig. 1A), Ullrich and colleagues at the MPI in Frankfurt established unequivocally that Pi is reabsorbed from the primary urine along the proximal tubule with highest rates occurring in the early part of the tubule [2]. These in vivo epithelial transport assays demonstrated that reabsorption of Pi in the proximal tubules is strictly dependent on the presence of sodium ions in the luminal medium (Fig. 1B). Importantly, the Frankfurt group provided the first insights into the regulation of renal Pi reabsorption. Their experiments revealed that parathyroid hormone (PTH) downregulates the rate of Pi reabsorption and that the reabsorption rate is influenced by dietary Pi [50, 51] (Fig. 1C). From such in vivo studies, it became clear that proximal tubular reabsorption of Pi was indeed not paracellular, but rather involved a first transport step through the apical (brush border) membrane of the epithelia and a subsequent exit step across the basolateral membrane [37, 50]. In the following years, the interest focused on functional aspects of the transport mechanism at the cell membranes facing either the tubular lumen or the peritubular interstitium. A novel technique, free-flow electrophoresis, allowed the isolation of brush-border and basolateral membrane vesicles simultaneously and enabled a direct comparison of the two transport steps [21, 25]. However, the isolated basolateral membranes (BLMV) were of random orientation and represented a mix of “inside out” and “outside out” vesicles, thus making the basolateral Pi exit step challenging to investigate [18]. The findings obtained with free-flow separated vesicles were complemented by transport studies with basolateral membrane vesicles isolated by Percoll gradient [18]. These seminal experiments established that the Na+ dependent step is localized at the brush border membrane and the basolateral translocation of Pi is Na+ independent [19]. Thus, proximal tubular reabsorption of Pi could be described as a classical secondary active transport process that relies on the Na/K-ATPase to establish the necessary electrochemical driving force. To conceptualize these findings, a model was proposed whereby the transmembrane Na+ gradient drives the reabsorption of Pi via a Na+-coupled Pi cotransporter system (Fig. 3). A Na+-independent mechanism (possibly an anion-exchanger) would then complete the net transcellular Pi movement from the primary urine to the peritubular space. Whereas the identity of the apical transport protein was soon to be established in Zurich, the membrane proteins mediating the basolateral step are still poorly understood, although the recent emergence of the retrovirus receptor (XPR1) as a candidate for this role appears most promising [1, 16].
Fig. 1

Evidence for transepithelial Pi transport in renal tissue demonstrated by microperfusion assays on the intact kidney. A) General features of the experimental setup to perform microperfusion of superficial renal proximal tubules. Photograph shows the rat preparation: A: animal table; B: rat; C: inner kidney cup; D: outer kidney cup; E: outer cup holder; F: perfusion tube; G: suction; H: catheter in ureter; K: oil-filled micropipette (adapted and modified from [49]). Inset summarizes different aspects of micropuncture techniques showing pipettes for collection of tubule fluid (1, 3) tubule perfusion (2), and perfusion of peritubular capillaries (4). In the standing oil droplet approach, an oil droplet is first injected using a double-barrelled pipette (not shown) and the droplet split (black areas) by injection of the test solution that also contains a non-reabsorbable solute. Modified from Fig. 1, ref. [40]. B) Transport of Pi is Na+-dependent determined at two positions along the proximal tubule: in the presence of Na+ on either side of the epithelia, achieved by means of double microperfusion involving continuous perfusion of peritubular capillaries and stop flow microperfusion of the proximal tubule [2]. The intraluminal Pi concentration (expressed as a % of the initial 2 mM concentration after 45 s exposure) is significantly reduced, whereas in the absence of Na+, there is a small increase in Pi. Data taken from [2]. C) Effect of parathyroid hormone (PTH) on Pi transport in the early and late rat proximal tubule using the double microperfusion method as in B). The luminal perfusate contained initially 2 mM Pi; hence, a concentration difference (Δc) of maximally 2 mM could be detected indicating that all Pi is reabsorbed. When PTH was given intravenously, this led to ~ 40% decrease of Pi transport in both early and late tubules within minutes (maximum at 15 min). Empty bars represent control and filled bars show effect of PTH given intravenously. Data taken from [51]

The pre-cloning Pi transport studies were advanced significantly by means of a modified procedure to isolate the proximal tubular brush border membrane vesicles (BBMVs). This was adapted from a protocol developed from rabbit renal BBMV [7] and yielded pure and abundant BBMV and involved only a few differential centrifugation steps [6]. The isolated (renal) BBMV were of “right side out” orientation [18] and allowed the study of the transport characteristics in considerable detail in terms of kinetics and regulation. The first studies of Pi transport performed in the Ullrich laboratory (MPI, Frankfurt) using renal and intestinal tissue [5, 25] and later by the Saktor laboratory (NIH, Baltimore) using renal tissue [41] established kinetic hallmarks of the transporter that would later serve as reference values for the cloned transporters. These laboratories confirmed the strict Na+-dependence of transport and measured an apparent half-maximum concentration (Km) of approximately 0.1 mM [25, 41] (Fig. 2). Furthermore, it was confirmed that Pi influx into BBMV was pH dependent; however, there was no indication of a net movement of charge (i.e., electrogenic transport) [25, 41]. Indeed, by having an excess of positive charge (i.e., 3 Na+ to 1 divalent Pi) as would be eventually shown experimentally [9, 14], the cotransport rate mediated by NaPi-IIa and NaPi-IIb would be enhanced by the inside negative membrane potential to provide an additional driving force. Meanwhile, these BBMV studies also allowed the investigation of various inhibitors of Na/Pi-cotransport, such as phosphonoformic acid [46, 47]. In addition, dietary or hormonal interventions prior to BBMV isolation confirmed the inhibitory effect of PTH and the influence of dietary Pi as observed in microperfusion studies [36, 44] (Fig. 2). Importantly, the inhibitory/stimulatory effects were conserved in isolated membrane vesicles, i.e., independent of the cellular/organ context, and were manifest as changes in maximal transport rate (Vmax) but not Km [31]. These observations underpinned the fundamental property of BBMV Pi transport, namely that the rate of Pi reabsorption was most likely proportional to the number of active transporters and not dependent on functional changes in the transporter itself.
Fig. 2

Pi transport assays performed with isolated proximal tubular brush border membrane vesicles (BBMVs). A) Freeze fracture micrograph of BBMVs prepared from rat renal BBMVs. See [6, 18] for details and methodology. B) Effect of ion gradients on Pi transport. If the intravesicular space is Na+-free, 32Pi uptake initially overshoots and falls to an equilibrium value as the vesicles become loaded with Na+ (Na+ unloaded). No overshoot is observed with vesicles preloaded with Na+ (Na+ preloaded). With a K+ gradient uptake is significantly reduced and not affected by preloading (open vs filled triangles). For more details, see original reference [25]. C) Time dependence of 32Pi uptake into BBMVs demonstrating the effect of dietary Pi on BBMV activity. As in B) the uptake peaks and decreases as the vesicles become loaded with substrate, and the uptake eventually reaches an equilibrium exchange condition identical to the mannitol control. For vesicles prepared from animals on a low Pi diet, the peak uptake is significantly enhanced, consistent with having greater number of carriers expressed, as would be later shown by immunostaining of proximal tubules and protein analysis (e.g., [37]). Data modified from [44]

In addition to the kidney, absorption of Pi along the small intestine also contributes to whole body Pi homeostasis [35]. Studies using isolated small intestinal membrane vesicles provided evidence for a Na+-dependent and a Na+-independent pathway across the brush border and basolateral membranes of enterocytes [11, 38]. Interestingly, the Na+-dependent component showed a divergent pH dependence compared to the renal transporter with significant transport activity at pH < 7. Thus, for both, proximal tubules and small intestine, it was assumed that a single renal and intestinal Na+-dependent transport system at the brush border membrane was being observed. Figure 3 depicts a schematic of the hypothesized single pathway of Pi through the apical membrane of proximal tubules. Based on the experimental evidence at the time, this model proposed a 2 Na+:1 Pi stoichiometry and an allosteric regulation by protons that compete with the interaction of the Na+ ions [17]. As divalent Pi is the prevalent form at physiological pH, it was also assumed that the transport process was electroneutral, contradicting previous studies with intact renal tubules in which electrogenicity was observed [15]. This model has since undergone several revisions as detailed in [13].
Fig. 3

Pre-cloning model of the molecular mechanism from 1986 of renal proximal tubular Na-dependent Pi reabsorption that accounts for apical entry of Pi [17]. At the apical membrane the interaction of 2 Na+ ions from the external medium allows divalent Pi to bind and be translocated by means of a secondary active carrier. Protons compete with Na+ ions to account for the pH dependence of transport. Studies on the cloned transporter have led to the revision of this model (see [13]). Basolateral exit of Pi was proposed to be mediated by Na+-independent anion carrier (yellow) and the Na/K-ATPase maintains the driving force (purple)

The molecular identity of the proteins involved in Pi transport was a pressing question and attempts were undertaken to identify the transporter by biochemical means in the pre-cloning era. For example, given that PTH affects renal Pi reabsorption and Na+/Pi-cotransport in BBMVs in a cAMP-dependent manner, phosphorylation studies were performed with isolated BBMVs. These studies demonstrated cAMP-dependent changes of BBMV protein-phosphorylation, but the identity of those phospho-proteins remained unknown [20].

The cloning of NaPi-IIa [32, 33] heralded a new era in the field by enabling the study of the transport mechanisms/characteristics in isolation after injection of cRNA into oocytes of Xenopus laevis [13]. By knowing the amino acid sequence, specific antibodies could be raised to enable specific in situ protein detection of each isoform. Studies using these antibodies allowed the detailed characterization of the cellular mechanisms that are involved in the physiological regulation by an increasing number of hormones. It was also possible to answer questions regarding the interaction with other proteins that are involved in the cellular regulation of Na+/Pi-cotransport.

The collection of invited reviews in this Special Issue gives a comprehensive summary of the impressive progress that has been made in the Pi field since the early cloning days. It is our hope that these articles will provide a useful overview for experts and non-experts alike and stimulate continued research in the Pi field. The reviews have been grouped according to five themes: Molecular and Mechanistic Aspects, including interacting proteins [12, 13, 23, 43], Physiological Regulation [26, 27, 48], Human Mutations/Clinical Aspects and Diseases [4, 30], Non-renal Roles for SLC34 Proteins [3, 34], and Comparative Aspects [39, 52].

Footnotes

  1. 1.

    Historically, the nomenclature of the cloned, mammalian Pi transporters followed a strictly chronological convention, beginning with the type 1 (NaPi-I) [10, 53] (since shown to be related to an anion conductance and not directly mediate Na-dependent Pi transport [8]); the type II (NaPi-II [33] or npt2) and the type III (NaPi-III [28, 29], or Pit-1,2). The widely used solute carrier (SLC) nomenclature [22] assigns the type I transporters to the SLC17 gene family; type II Na-Pi transporters to SLC34 and type III transporters to SLC20, respectively. The SLC system is increasingly used, i.e., SLC34A1, SLC34A2, and SLC34A3 for the human type II transporters NaPi-IIa, NaPi-IIb, and NaPi-IIc, respectively. The structurally similar isoforms are grouped into the same sub-family (SLC34A) with individual indices (1, 2, 3). This nomenclature is easily applicable to most vertebrates; it only becomes less clear in the case of fish that have undergone genome duplications followed by lineage specific gene losses.

Notes

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Heini Murer
    • 1
  • Jürg Biber
    • 1
    Email author
  • Ian C. Forster
    • 2
  • Andreas Werner
    • 3
  1. 1.Department of PhysiologyUniversity of ZurichZürichSwitzerland
  2. 2.Florey Institute of Neuroscience and Mental HealthParkvilleAustralia
  3. 3.Epithelial Research Group, Newcastle UniversityInstitute for Cell and Molecular BiosciencesNewcastleUK

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