Soon after the discovery that mutations in fibroblast growth factor-23 (FGF23) are the genetic cause of autosomal-dominant hypophosphatemic rickets , it was shown that FGF23 reduces phosphate reabsorption from urine through a downregulation of sodium phosphate cotransporters in renal proximal tubular epithelial cells [2–4]. It is now firmly established that FGF23 is a phosphaturic hormone secreted by osteocytes and osteoblasts, and that excessive amounts of intact FGF23 in the blood stream lead to renal phosphate wasting .
Apart from its suppressive effects on renal transcellular phosphate transport, FGF23 is also a potent down-regulator of 1α-hydroxylase expression in renal proximal tubules, thereby suppressing the production of the biologically active vitamin D hormone, 1α,25-dihydroxyvitamin D3. The secretion of FGF23 in bone is stimulated by the vitamin D hormone and by increased extracellular phosphate, forming a feedback loop between bone and kidney .
Binding of FGF23 to target cells requires a receptor complex consisting of FGF receptors and the transmembrane protein αKlotho [6,7], hereafter referred to as Klotho. There are four different FGFRs, and it is currently not entirely clear which FGFRs are responsible for the actions of FGF23 in different cell types. Solid evidence has been provided that FGF23 signals through a FGF receptor-1c/Klotho complex . Klotho may also, however, bind to FGFR3 and 4 . FGF receptors are tyrosine kinase receptors, leading to phosphorylation of downstream molecules when activated through ligand binding .
The purpose of this review was to highlight the recent advances in the area of FGF23-regulated solute transport in the kidney. Significant progress has been made in the further characterization of the signaling pathways involved in the FGF23-induced inhibition of phosphate transport in proximal tubular epithelium, and major new functions of FGF23 in solute transport have been discovered in distal renal tubules.
PROXIMAL TUBULAR PHOSPHATE TRANSPORT
Renal phosphate transporters play a key role in phosphate homeostasis [9▪]. Although it has been clear since its discovery that FGF23 is a phosphaturic hormone suppressing the membrane expression of phosphate transporters in renal proximal tubules [2–4], the molecular mechanism underlying this action had long remained elusive. It was previously thought that Klotho is expressed mainly in the distal tubule . We, however, recently showed that Klotho is expressed in the basolateral membrane in renal proximal tubular epithelium, and that FGF23 directly downregulates membrane expression of the sodium-phosphate cotransporter NaPi-2a in proximal tubular cells by serine phosphorylation of the scaffolding protein Na+/H+ exchange regulatory cofactor (NHERF)-1 through ERK1/2 and serum/glucocorticoid-regulated kinase-1 (SGK1) signaling in a Klotho-dependent fashion . The other major phosphaturic hormone, parathyroid hormone, also downregulates membrane expression of NaPi-2a by phosphorylation of NHERF-1, leading to internalization and degradation of NaPi-2a [12,13]. Because proximal tubular cells from NHERF-1 null mice are resistant to the inhibitory action of FGF23 on phosphate transport , NHERF-1 appears to be an essential target of the FGF23-induced signaling pathway. The intracellular signaling pathways downstream of FGFRs are, however, only partially known.
It is well established that FGF23 suppresses the apical membrane abundance of NaPi-2a and NaPi-2c [3,15,16], thereby regulating apical phosphate entry into the epithelial cells. Whether FGF23 also regulates other phosphate transporters such as Pit-1 is currently not known. Recent evidence revealed that the role of NaPi-2c is minor in this context under physiological conditions. Myakala et al.[17▪] showed by a renal-specific and inducible depletion of NaPi-2c that NaPi-2c is not essential for the maintenance of phosphate homeostasis under steady-state conditions in mice. Kidney-specific deletion of NaPi-2c neither changed plasma phosphate and urinary phosphate excretion, nor circulating Fgf23 and parathyroid hormone levels, indicating that depletion of NaPi-2c does not affect phosphate homeostasis in vivo in mice [17▪]. Thus, although FGF23 regulates NaPi-2a and 2c in parallel, the phosphaturic action of FGF23 is mainly determined by downregulation of the apical membrane abundance of NaPi-2a, at least in mice.
Recent progress has been made regarding the FGF receptors responsible for the phosphaturic action of FGF23. There is firm evidence that proximal tubular epithelial cells express FGFR1, 3, and 4, but not 2 [11,18]. Based on the work by Urakawa et al., the FGFR1 isoform FGFR1c may be the main FGF receptor forming receptor complexes with Klotho. Other FGF receptors may, however, also be involved in the FGF23-induced regulation of phosphate cotransporters in the kidney.
Gattineni et al.[19▪▪] used compound mutant mice with a kidney-specific conditional knockout of Fgfr1 and a global deletion of Fgfr4, and compared these compound mutants with Fgfr4−/− and wildtype mice to determine the FGF receptors responsible for the hypophosphatemic action of FGF23. Fgfr1−/−/Fgfr4−/− compound mutants displayed ∼50-fold higher circulating intact Fgf23 levels than wildtype controls, together with elevated serum phosphate, and elevated Na-Pi cotransporter-2c protein expression, suggesting that Fgf23 was no longer able to decrease phosphate reabsorption in the kidney. Moreover, administration of recombinant Fgf23 to Fgfr1−/−/Fgfr4−/− compound mutants failed to increase renal MAPK phosphorylation in whole kidney lysates, 1 h postinjection [19▪▪]. Taken together, the study by Gattineni et al.[19▪▪] demonstrated that combined deletion of FGFR1 and 4 completely abolishes the phosphaturic action of FGF23 in vivo. Based on this work, the phosphaturic action of FGF23 is mediated through FGFR1 and FGFR4. Earlier work of the same group suggested that FGFR1 is the predominant receptor mediating the hypophosphatemic actions of FGF23 in vivo with FGFR4 playing only a minor role . As mentioned above, it is still controversial whether Klotho and FGFR4 can form receptor complexes for FGF23 binding. Whether the signaling mechanisms downstream of FGFR1 and 4 are different, also needs further clarification.
As far as the intracellular signaling mechanisms are concerned, Umbach et al.[20▪▪] made the interesting observation that global Janus kinase 3 (JAK3) knockout mice are characterized by increased circulating Fgf23 and vitamin D hormone, as well as increased urinary excretion of phosphate. Furthermore, coexpression of NaPi-2a and JAK3 augmented phosphate uptake in Xenopus oocytes, relative to expression of NaPi-2a alone. Although it is clear that these results need to be confirmed by a kidney-specific deletion of JAK3, the findings reported by Umbach et al.[20▪▪] may be the first evidence for an involvement of JAK signaling in the FGF23-induced regulation of phosphate transporters and 1α-hydroxylase expression.
There are also interesting new developments in our ability to modulate FGF23 signaling by pharmacological inhibitors. Huang et al.[21▪] screened a phage display library using the C-terminal part of FGF23 which is involved in binding of intact FGF23 to the FGFR1c-Klotho complex . They found a peptide with high homology to FGFR1c. This peptide blocked FGF23-induced ERK phosphorylation and regulation of NaPi-2a and NaPi-2c in opossum kidney cells in vitro, suggesting that inhibition of FGF23 signaling may not only be possible by anti-FGF23 antibodies [23▪], but also by peptide-mediated, specific inhibition of FGF23 binding to its receptor complex.
In conclusion, FGF23 suppresses reabsorption of filtered phosphate in renal proximal tubular epithelium by a Klotho-dependent, FGFR1 and probably to a lesser extent FGFR4-mediated signaling mechanism. The current knowledge about FGF23 signaling in proximal tubular epithelium is schematically shown in Fig. 1. The FGF23-induced intracellular signaling cascades regulating membrane expression of phosphate transporters are only partially known at present. An improved understanding of the molecular mechanisms involved in FGF23 signaling in proximal tubular epithelial cells may result in the development of new therapeutic tools for the management of hypophosphatemic disorders caused by excessive circulating intact FGF23, an important clinical need.
DISTAL TUBULAR CALCIUM AND SODIUM TRANSPORT
It was reported many years ago that the earliest renal changes in the activation of ERK1/2 after injection of FGF23 in vivo occur in distal tubules . It was, however, thought at that time that FGF23 would act on the distal tubule to generate an endocrine or paracrine secondary signal that, in turn, would signal back to the proximal tubule to downregulate transcellular phosphate transport. We recently reported that the FGF23-induced phosphorylation of ERK1/2 in distal tubular epithelium is part of a signaling cascade that regulates calcium and sodium transport in the distal nephron [25▪▪,26▪▪]. Thus, FGF23 has parallel and independent effects in proximal and distal renal tubules.
The epithelial calcium channel transient receptor potential vannilloid-5 (TRPV5) is a glycoprotein essential for entry of calcium in renal epithelial cells. Apical membrane abundance of fully glycosylated TRPV5 is the rate-limiting step in distal renal tubular transcellular calcium transport . It was reported earlier that soluble Klotho is a regulator of TRPV5 by stabilizing the interaction between glycosylated TRPV5 and membrane-bound galectin through its putative glycosidase activity, thereby preventing endocytosis [28,29]. More recently, it was suggested that Klotho may also enhance forward trafficking of TRPV5 through its sialidase activity from inside the renal epithelial cells .
We recently identified FGF23 as a regulator of TRPV5 in renal distal tubules, acting through the FGFR/Klotho receptor complex in a Klotho-dependent fashion [25▪▪]. In loss-of-function mouse models, Klotho deficiency and Fgf23 deficiency resulted in almost identical decreases in renal TRPV5 expression and concomitant increases in renal calcium excretion [25▪▪]. In gain-of-function models, injection of mice with recombinant FGF23 upregulated TRPV5 expression in the distal tubular apical membrane, and profoundly decreased renal calcium excretion in a Klotho-dependent manner [25▪▪]. Another important finding in this study [25▪▪] was that FGF23 signaling led to phosphorylation and cellular redistribution of with-no-lysine kinase 4 (WNK4), one of the central molecules regulating TRPV5 trafficking in renal distal tubules [31–33]. Additional in-vitro experiments using isolated distal tubular segments, live calcium imaging in kidney slices, and reconstitution of the signaling pathway in MDCK cells showed that FGF23 acts directly on distal tubular cells, increasing TRPV5 membrane expression and calcium uptake through an intracellular signaling cascade involving ERK1/2, SGK1, and WNK4. WNK kinases act as a complex of WNK1, 3, and 4, to control the intracellular transport of membrane proteins . It is currently unknown whether FGF23 signaling involves only WNK4 or other members of the WNK family as well.
Taken together, the study by Andrukhova et al.[25▪▪] identified FGF23 as a calcium-conserving hormone in the kidney. This finding may be of major pathophysiological relevance for diseases such as chronic kidney disease (CKD) in which FGF23 is chronically elevated because of phosphate retention and hyperphosphatemia. Hyperphosphatemia per se has been identified as a risk factor for vascular calcification in patients with CKD  and cardiovascular disease in normal patients . Although clinical confirmation of our findings in mice is currently lacking, the hyperphosphatemia-driven increase in circulating FGF23 may further contribute to calcium accumulation and vascular calcifications in CKD patients through augmented renal calcium conservation.
The novel link between FGF23 signaling and WNK4 activation in distal tubular epithelium led us to hypothesize that FGF23 may not only regulate the membrane abundance of TRPV5 but also of the Na+:Cl− cotransporter NCC in distal renal tubules. WNK4 is a key regulator of distal tubular membrane abundance of NCC [37▪▪]. Together with the epithelial calcium channel ENaC, NCC is responsible for Na+ reabsorption in the distal nephron.
We recently reported that Fgf23 and Klotho-deficient mice showed decreased membrane expression of NCC in renal distal tubules, leading to renal sodium wasting, reduced plasma volume, and lower blood pressure despite elevated aldosterone secretion [26▪▪]. Conversely, injection of recombinant FGF23 into normal mice resulted in renal sodium retention, plasma expansion, hypertension, and heart hypertrophy by upregulation of renal NCC expression in a Klotho-dependent manner [26▪▪]. Cotreatment with the NCC inhibitor chlorothiazide abrogated the FGF23-induced hypertension [26▪▪]. In-vitro experiments confirmed that FGF23 directly regulates NCC membrane abundance and activity in distal renal tubules through the FGF receptor 1c/αKlotho–ERK1/2–SGK1–WNK4 signaling axis [26▪▪]. When we treated normal mice on different sodium diets with recombinant FGF23, we found that a low-sodium diet aggravated the hypertensive effects of FGF23, probably because intracellular signaling of FGF23 and of the other major sodium-conserving hormone aldosterone converge on SGK1 in distal renal tubules. It is well known that aldosterone increases SGK1 expression and activity in the distal nephron, leading to augmented membrane abundance of ENaC and subsequently increased renal tubular Na+ reabsorption . Moreover, aldosterone can activate NCC through a signaling mechanism involving SGK1, WNK4, and STE20/SPS-1-related proline/alanine-rich kinase [39–41]. Therefore, it is possible that aldosterone and FGF23 have synergistic effects on activation of transporters involved in Na+ reabsorption in renal distal tubules.
Based on our findings [26▪▪], FGF23 is not only a phosphaturic, but also a Na+-conserving hormone involved in volume and blood pressure homeostasis. Because sodium homeostasis is tightly coupled to volume regulation and blood pressure, this finding may help to explain why circulating FGF23 is positively and dose-dependently associated with CKD progression, left ventricular hypertrophy, vascular calcifications, and mortality in CKD patients [42,43]. The finding that FGF23 and aldosterone signaling converge on SGK1 in the distal nephron [26▪▪] may have important implications for clinical medicine, because the typically elevated aldosterone levels in CKD patients  may additionally augment the effects of FGF23 on Na+ retention. The Na+-conserving function of FGF23 may also have implications for the pathophysiology of hypertension in normal individuals, because high-phosphate diets may stimulate FGF23 secretion and Na+ retention.
The novel link between FGF23 and sodium homeostasis has not been explored yet in clinical studies. A recent clinical study, however, indirectly confirmed the possible interaction between the renin–angiotensin–aldosterone system and FGF23. In a dietary intervention study in patients with CKD, Humalda et al.[45▪▪] found that high baseline plasma carboxyterminal FGF23 levels impaired the positive effect of a low-sodium diet in combination with RAAS blockade on urinary protein excretion. Although this finding needs to be confirmed in larger studies, it may suggest that aldosterone and FGF23 signaling interact also in humans.
In conclusion, our recent studies indicate that FGF23 directly acts on distal renal tubules to increase the reabsorption of calcium and sodium ions. Figure 2 summarizes schematically what is currently known about FGF23 signaling and the crosstalk between FGF23 and aldosterone signaling in distal tubular epithelium.
Recent advances in the field of FGF23-regulated solute transport in the kidney have shown that FGF23 has independent effects on proximal and distal tubular epithelium. FGF23 suppresses phosphate reabsorption in renal proximal tubular epithelium by a Klotho-dependent, FGFR1, and, probably to a lesser extent, FGFR4-mediated signaling mechanism. In distal tubular epithelium, FGF23 signaling activates WNK4 in a Klotho-dependent manner, leading to augmented membrane expression of TRPV5 and NCC and subsequently increased reabsorption of sodium and calcium ions. The sodium and calcium-conserving functions of FGF23 may have major pathophysiological implications for conditions with chronically increased circulating FGF23 concentrations such as CKD, but may also provide a novel putative link between phosphate intake and hypertension in normal individuals. Clearly, more work is necessary to define the detailed molecular mechanisms of FGF23 signaling in renal epithelia, and to better characterize the crosstalk between PTH and FGF23 signaling in proximal, and especially between aldosterone and FGF23 signaling in distal renal tubules.
Financial support and sponsorship
This work was supported by a grant from the Austrian Science Fund (FWF 24186-B21) to R.G.E.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
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