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FGF23 regulation of renal tubular solute transport

Erben, Reinhold G.; Andrukhova, Olena

Current Opinion in Nephrology and Hypertension: September 2015 - Volume 24 - Issue 5 - p 450–456
doi: 10.1097/MNH.0000000000000145
MOLECULAR CELL BIOLOGY AND PHYSIOLOGY OF SOLUTE TRANSPORT: Edited by Alan S.L. Yu
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Purpose of review Fibroblast growth factor-23 (FGF23) is a bone-derived hormone known to suppress phosphate reabsorption in the kidney. The purpose of this review was to highlight the recent advances in the area of FGF23-regulated solute transport in the kidney.

Recent findings Recent evidence suggests that FGF23 suppresses phosphate reabsorption in renal proximal tubular epithelium by a Klotho-dependent, FGF receptor (FGFR)-1 and FGFR4-mediated signaling mechanism that may also involve Janus kinase 3. Moreover, it was recently established that FGF23 signaling in the distal renal tubule targets with-no-lysine kinase-4 (WNK4), a key molecule in the regulation of solute transport in the distal nephron. By targeting WNK4, FGF23 has been shown to increase the membrane abundance of the epithelial calcium channel TRPV5 and of the sodium-chloride cotransporter NCC, resulting in augmented renal calcium and sodium reabsorption.

Summary 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. The calcium- and sodium-conserving functions of FGF23 may have major implications for the pathophysiology of cardiovascular diseases.

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University of Veterinary Medicine Vienna, Vienna, Austria

Correspondence to Reinhold G. Erben, MD, DVM, Department of Biomedical Sciences, Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria. Tel: +43 1250774550; fax: +43 1250774599; e-mail: Reinhold.Erben@vetmeduni.ac.at

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INTRODUCTION

Soon after the discovery that mutations in fibroblast growth factor-23 (FGF23) are the genetic cause of autosomal-dominant hypophosphatemic rickets [1], 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 [5].

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 [5].

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 [6]. Klotho may also, however, bind to FGFR3 and 4 [7]. FGF receptors are tyrosine kinase receptors, leading to phosphorylation of downstream molecules when activated through ligand binding [8].

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.

Box 1

Box 1

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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 [10]. 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 [11]. 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 [14], 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.[6], 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 [18]. 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 [22]. 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.

FIGURE 1

FIGURE 1

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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 [24]. 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 [27]. 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 [30].

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 [34]. 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 [35] and cardiovascular disease in normal patients [36]. 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 [38]. 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 [44] 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.

FIGURE 2

FIGURE 2

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CONCLUSION

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.

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Acknowledgements

None.

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Financial support and sponsorship

This work was supported by a grant from the Austrian Science Fund (FWF 24186-B21) to R.G.E.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

1. The ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 2000; 26:345–348.
2. Shimada T, Mizutani S, Muto T, et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A 2001; 98:6500–6505.
3. Shimada T, Hasegawa H, Yamazaki Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004; 19:429–435.
4. Shimada T, Yamazaki Y, Takahashi M, et al. Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism. Am J Physiol Renal Physiol 2005; 289:F1088–F1095.
5. Martin A, David V, Quarles LD. Regulation and function of the FGF23/klotho endocrine pathways. Physiol Rev 2012; 92:131–155.
6. Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006; 444:770–774.
7. Kurosu H, Ogawa Y, Miyoshi M, et al. Regulation of fibroblast growth factor-23 signaling by Klotho. J Biol Chem 2006; 281:6120–6123.
8. Ornitz DM, Itoh N. The fibroblast growth factor signaling pathway. Wiley Interdiscip Rev Dev Biol 2015; 4:215–266.
9▪. Lederer E. Renal phosphate transporters. Curr Opin Nephrol Hypertens 2014; 23:502–506.

Excellent recent review about renal phosphate transporters.

10. Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997; 390:45–51.
11. Andrukhova O, Zeitz U, Goetz R, et al. FGF23 acts directly on renal proximal tubules to induce phosphaturia through activation of the ERK1/2-SGK1 signaling pathway. Bone 2012; 51:621–628.
12. Deliot N, Hernando N, Horst-Liu Z, et al. Parathyroid hormone treatment induces dissociation of type IIa Na+-P(i) cotransporter-Na+/H+ exchanger regulatory factor-1 complexes. Am J Physiol Cell Physiol 2005; 289:C159–C167.
13. Weinman EJ, Biswas RS, Peng G, et al. Parathyroid hormone inhibits renal phosphate transport by phosphorylation of serine 77 of sodium-hydrogen exchanger regulatory factor-1. J Clin Invest 2007; 117:3412–3420.
14. Weinman EJ, Steplock D, Shenolikar S, et al. FGF-23-mediated inhibition of renal phosphate transport in mice requires NHERF-1 and synergizes with PTH. J Biol Chem 2011; 286:37216–37221.
15. Larsson T, Marsell R, Schipani E, et al. Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. Endocrinology 2004; 145:3087–3094.
16. Shimada T, Urakawa I, Yamazaki Y, et al. FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem Biophys Res Commun 2004; 314:409–414.
17▪. Myakala K, Motta S, Murer H, et al. Renal-specific and inducible depletion of NaPi-IIc/Slc34a3, the cotransporter mutated in HHRH, does not affect phosphate or calcium homeostasis in mice. Am J Physiol Renal Physiol 2014; 306:F833–F843.

These articles show that renal NaPi-2c has only a minor role in phosphate homeostasis in mice.

18. Gattineni J, Bates C, Twombley K, et al. FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am J Physiol Renal Physiol 2009; 297:F282–F291.
19▪▪. Gattineni J, Alphonse P, Zhang Q, et al. Regulation of renal phosphate transport by FGF23 is mediated by FGFR1 and FGFR4. Am J Physiol Renal Physiol 2014; 306:F351–F358.

This study shows that FGF23-induced downregulation of renal transcellular phosphate transport is mediated by signaling through FGFR1 and FGFR4.

20▪▪. Umbach AT, Zhang B, Daniel C, et al. Janus kinase 3 regulates renal 25-hydroxyvitamin D 1alpha-hydroxylase expression, calcitriol formation, and phosphate metabolism. Kidney Int 2015; 87:728–737.

This study suggests that JAK3 is a regulator of renal 1α-hydroxylase expression and phosphate transport.

21▪. Huang T, Lin X, Li Q, et al. Selection of a novel FGF23-binding peptide antagonizing the inhibitory effect of FGF23 on phosphate uptake. Appl Microbiol Biotechnol 2015; 99:3169–3177.

This study reports a peptide with high homology to FGFR1c, blocking the effects of FGF23 signaling on phosphate transporters.

22. Yamazaki Y, Tamada T, Kasai N, et al. Anti-FGF23 neutralizing antibodies show the physiological role and structural features of FGF23. J Bone Miner Res 2008; 23:1509–1518.
23▪. Fukumoto S. Antifibroblast growth factor 23 antibody therapy. Curr Opin Nephrol Hypertens 2014; 23:346–351.

Up-to-date source of information about anti-FGF23 antibody therapy.

24. Farrow EG, Davis SI, Summers LJ, et al. Initial FGF23-mediated signaling occurs in the distal convoluted tubule. J Am Soc Nephrol 2009; 20:955–960.
25▪▪. Andrukhova O, Smorodchenko A, Egerbacher M, et al. FGF23 promotes renal calcium reabsorption through the TRPV5 channel. EMBO J 2014; 33:229–246.

This article shows that FGF23 is a calcium-conserving hormone by stimulating TRPV5 membrane transport via WNK4 activation in renal distal tubular epithelium.

26▪▪. Andrukhova O, Slavic S, Smorodchenko A, et al. FGF23 regulates renal sodium handling and blood pressure. EMBO Mol Med 2014; 6:744–759.

This study identifies FGF23 as a sodium-conserving hormone involved in blood pressure regulation.

27. Lambers TT, Bindels RJ, Hoenderop JG. Coordinated control of renal Ca2+ handling. Kidney Int 2006; 69:650–654.
28. Chang Q, Hoefs S, Van Der Kemp AW, et al. The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel. Science 2005; 310:490–493.
29. Cha SK, Ortega B, Kurosu H, et al. Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1. Proc Natl Acad Sci U S A 2008; 105:9805–9810.
30. Wolf MT, An SW, Nie M, et al. Klotho up-regulates renal calcium channel transient receptor potential vanilloid 5 (TRPV5) by intra- and extracellular N-glycosylation-dependent mechanisms. J Biol Chem 2014; 289:35849–35857.
31. Jiang Y, Ferguson WB, Peng JB. WNK4 enhances TRPV5-mediated calcium transport: potential role in hypercalciuria of familial hyperkalemic hypertension caused by gene mutation of WNK4. Am J Physiol Renal Physiol 2007; 292:F545–F554.
32. Jiang Y, Cong P, Williams SR, et al. WNK4 regulates the secretory pathway via which TRPV5 is targeted to the plasma membrane. Biochem Biophys Res Commun 2008; 375:225–229.
33. Cha SK, Huang CL. WNK4 kinase stimulates caveola-mediated endocytosis of TRPV5 amplifying the dynamic range of regulation of the channel by protein kinase C. J Biol Chem 2010; 285:6604–6611.
34. McCormick JA, Yang CL, Ellison DH. WNK kinases and renal sodium transport in health and disease: an integrated view. Hypertension 2008; 51:588–596.
35. Scialla JJ, Lau WL, Reilly MP, et al. Fibroblast growth factor 23 is not associated with and does not induce arterial calcification. Kidney Int 2013; 83:1159–1168.
36. Dhingra R, Sullivan LM, Fox CS, et al. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med 2007; 167:879–885.
37▪▪. Bazua-Valenti S, Gamba G. Revisiting the NaCl cotransporter regulation by With No-lysine Kinases. Am J Physiol Cell Physiol 2015; 308:C779–C791.doi: 10.1152/ajpcell.00065.2015. [Epub ahead of print].

Excellent review about the role of WNKs for renal tubular sodium reabsorption.

38. Chen SY, Bhargava A, Mastroberardino L, et al. Epithelial sodium channel regulated by aldosterone-induced protein sgk. Proc Natl Acad Sci U S A 1999; 96:2514–2519.
39. Rozansky DJ, Cornwall T, Subramanya AR, et al. Aldosterone mediates activation of the thiazide-sensitive Na-Cl cotransporter through an SGK1 and WNK4 signaling pathway. J Clin Invest 2009; 119:2601–2612.
40. van der Lubbe N, Lim CH, Meima ME, et al. Aldosterone does not require angiotensin II to activate NCC through a WNK4-SPAK-dependent pathway. Pflugers Arch 2012; 463:853–863.
41. Ko B, Mistry AC, Hanson L, et al. Aldosterone acutely stimulates NCC activity via a SPAK-mediated pathway. Am J Physiol Renal Physiol 2013; 305:F645–F652.
42. Juppner H, Wolf M, Salusky IB. FGF-23: more than a regulator of renal phosphate handling? J Bone Miner Res 2010; 25:2091–2097.
43. Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest 2011; 121:4393–4408.
44. Lattanzio MR, Weir MR. Does blockade of the renin-angiotensin-aldosterone system slow progression of all forms of kidney disease? Curr Hypertens Rep 2010; 12:369–377.
45▪▪. Humalda JK, Lambers Heerspink HJ, Kwakernaak AJ, et al. Fibroblast growth factor 23 and the antiproteinuric response to dietary sodium restriction during renin-angiotensin-aldosterone system blockade. Am J Kidney Dis 2015; 65:259–266.
Keywords:

calcium reabsorption; fibroblast growth factor-23; mineral homeostasis; phosphate transport; sodium reabsorption

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