Phosphate (Pi) is an essential mineral nutrient (Erem and Razzaque, 2018). Once absorbed and in circulation, Pi is utilized by cells for various structures and functions. Pi metabolism is regulated by a specific set of hormones to maintain physiological Pi concentrations. Fibroblast growth factor 23 (FGF23) is the chief hormone maintaining body Pi balance by promoting renal Pi excretion when Pi load is high (Fukumoto and Yamashita, 2007; Isakova et al., 2011). Dysregulation of this system causes either low (hypophosphatemia) or high (hyperphosphatemia) serum Pi levels (Farrow et al., 2011; White et al., 2001; Wolf, 2012). Hyperphosphatemic states can result from various conditions, including rare genetic disorders, such as familial tumoral calcinosis (FTC), and acquired diseases, such as chronic kidney disease (CKD), which are more frequent. Moreover, increased consumption of foods and drinks rich in Pi-based additives is expanding in Westernized diets, leading to excess dietary Pi intake (Carrigan et al., 2014; Gutiérrez et al., 2010a).

CKD patients have an increased risk of death that is attributable to complications such as inflammation, anemia, and skeletal muscle wasting (Amdur et al., 2016; Hoshino et al., 2020; Stenvinkel et al., 2016). The etiology of CKD-associated anemia is multifactorial and includes absolute iron deficiency and functional iron deficiency, with the latter caused by inflammatory cytokines including interleukin-6 (IL6) and interleukin-1β (IL1β). These inflammatory mediators can directly induce the release of the liver-hormone hepcidin, the master regulator of iron metabolism (Verga Falzacappa et al., 2007; Ganz and Nemeth, 2012; Kanamori et al., 2017). Hepcidin controls the flow of iron into circulation by regulating the iron exporter ferroportin (FPN) (Nemeth et al., 2004b). Hepcidin binding occludes FPN (Aschemeyer et al., 2018; Billesbølle et al., 2020) and induces its degradation, thereby restricting iron efflux into the circulation from iron recycling macrophages, a process also known as reticuloendothelial system (RES) blockade, and from duodenal enterocytes responsible for dietary iron absorption. Collectively, these events reduce serum iron levels (hypoferremia), limiting the supply of iron for erythrocyte production (Nemeth et al., 2004a).

Inflammatory cytokines such as IL6 and IL1β also act on skeletal muscle and induce muscle wasting, a comorbidity affecting 65% of CKD patients (Kovesdy et al., 2013; Li et al., 2009; Zhang et al., 2013). The loss of protein from muscle is ascribed to protein degradation by the ubiquitin–proteasome system, suppression of protein synthesis and impaired growth of new muscle fibers (Wang and Mitch, 2014). As pleotropic activities of IL6 and IL1β induce the production of myostatin, a pivotal mediator of skeletal muscle wasting, these actions foster the simultaneous induction of atrophy-related gene programs and reduced cellular responses to progrowth signals, which initiates protein synthesis suppression. Together, inflammation and myostatin advance these CKD-associated comorbidities which reduce the survival and quality of life of CKD patients (Zhang et al., 2011).

A prominent aspect of CKD is altered mineral metabolism, where hyperphosphatemia and excess serum FGF23 are factors associated with inflammation, anemia, and mortality (Mehta et al., 2017; Munoz Mendoza et al., 2017; Navarro-González et al., 2009; Tran et al., 2016). Drugs have been developed to control hyperphosphatemia, but reports show conflicting results about outcomes. Studies of the effects of dietary Pi restriction in animal models are scarce. Dietary interventions to lower Pi intake are challenging because they require long-term behavioral changes made more difficult by the lack of disclosure of Pi content of foods and beverages by the food industry (Gutiérrez and Wolf, 2010b).

All cell types rely on Pi for housekeeping roles, and metabolic Pi uptake is facilitated by three families of sodium–Pi (Na/Pi) cotransporters. Type III Na/Pi cotransporters, PiT-1 and PiT-2, are ubiquitously expressed and mediate cellular Pi homeostasis in all cells (Lederer and Miyamoto, 2012). Pathologic Pi accumulation in vasculature is mediated by PiT-1 and PiT-2, loading Pi into vascular smooth muscle cells where it activates signaling networks such as Ras/mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) (Chavkin et al., 2015; Turner et al., 2020; Zhao et al., 2011). These pathways provide plausible pathomechanisms that support excess Pi as a potential culprit behind the clinical association between hyperphosphatemia and CKD-associated vascular calcification.

Under physiologic conditions, bone-derived FGF23 targets the kidney to increase Pi excretion by activating its canonical signaling complex, fibroblast growth factor receptor 1 (FGFR1) and co-receptor Klotho (Czaya and Faul, 2019a). When FGF23 is in pathological excess, as found in dietary Pi overload or CKD, increased FGF23 targets the heart and liver by activating FGFR4, independently of Klotho (Faul et al., 2011; Grabner et al., 2015; Singh et al., 2016). This noncanonical mechanism recruits FGFR4 as a pathologic receptor mediating the effects of excess FGF23 to cause cardiac hypertrophy and promote inflammation (Faul et al., 2011; Grabner et al., 2015; Han et al., 2020; Leifheit-Nestler et al., 2017; Singh et al., 2016; Xiao et al., 2019). However, whether excess FGF23 and/or Pi directly contribute to functional iron deficiency or skeletal muscle wasting is unknown, and direct actions of excess Pi on the liver have not been studied to date.

In this study, we examine whether hyperphosphatemia and/or pathologic FGF23-FGFR4 signaling aggravates functional iron deficiency and skeletal muscle wasting, the common comorbidities in CKD. We expose mice constitutively lacking FGFR4 to hyperphosphatemia in the absence and presence of CKD. To further define the contribution of hyperphosphatemia, we subject Alport mice, a genetic model of progressive CKD, to a low Pi diet treatment. We identify a molecular mechanism in cultured mouse primary hepatocytes that links excess Pi to its actions on inflammation and iron metabolism, as increased inflammatory cytokines promote widespread pathologies and hepcidin production. Our findings reveal additional complications of hyperphosphatemia besides vascular calcification and identify plausible pathomechanisms underlying clinical associations between inflammation, anemia, and skeletal muscle wasting, which could be targeted therapeutically.

We report that hyperphosphatemia, either as a result of adenine-induced CKD or dietary Pi excess, increases inflammation to exacerbate anemia and skeletal muscle wasting (Figure 8). These complications are associated with increased liver Pi levels, which correlated with serum Pi concentrations. Supplying a low Pi diet treatment to Alport mice, a genetic model of CKD, results in beneficial outcomes that reduce functional iron deficiency and skeletal muscle wasting. Furthermore, our mechanistic in vitro studies indicate that Pi elevations induce hepatic production of IL6 and IL1β to increase hepcidin expression in hepatocytes, a potential causative link between hyperphosphatemia, anemia, and skeletal muscle dysfunction.

Figure 8

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Previously, we reported pathologic FGF23-FGFR4 signaling might contribute to excess inflammatory mediators (Singh et al., 2016), and we now followed up on the FGF23 inflammatory role in clinically relevant CKD models in vivo. Here, we examined wild-type (Fgfr4^+/+) and constitutive FGFR4 knockout (Fgfr4^−/−) mice subjected to adenine diet or a graded dietary Pi load. We found that on adenine, both Fgfr4^+/+ and Fgfr4^−/− mice show comparable macroscopic parameters (Table 1) and degrees of functional iron deficiency (Figure 1). These findings coincide with greater levels of liver Pi, which raises the possibility that pathologic Pi deposits, in tissues apart from the vasculature, may contribute to additional complications in CKD (Komaba and Fukagawa, 2016).

Clinical reports indicate CKD patients have dysregulated Pi handling (Chang et al., 2014; Isakova et al., 2009) and together with the consumption of foods and drinks rich in Pi-based additives, such as in a Westernized diet, extrarenal Pi accumulation may occur (Isakova et al., 2008). A recent study utilizing animal models supports this postulate, demonstrating that excess Pi leads to depositions into tissues such as the vasculature (Zelt et al., 2019). Moreover, a recent report indicates the major source of body Pi removed during hemodialysis in CKD patients, is from cells releasing intracellular Pi (Chazot et al., 2021). As the serum Pi compartment represents a small fraction of total body Pi, and the uptake of excess Pi by tissues is recognized as a detrimental trigger, it is important to examine the degree of pathologic Pi accumulation in nonvascular tissue and whether it exacerbates complications in CKD, such as anemia and muscle wasting.

We employed a graded Pi diet to study the effects of excess Pi on the liver (Figure 2). Studies show conflicting results toward renal and liver health, following supplementation of a high Pi diet (Baquerizo et al., 2003; Haut et al., 1980; Ugrica et al., 2021). In our study, no significant changes in macroscopic parameters were observed following dietary Pi overload (Table 2). Also, no pathologic changes in kidney (Figure 2—figure supplement 1) or liver were detected (Figure 2—figure supplement 2). However, mice on a 3% Pi diet exhibit increased liver inflammation and Hamp expression, which corroborates previous observation that high dietary Pi influences hepcidin production (Nakao et al., 2015). These results coincide with positive correlations between liver Pi and liver Hamp mRNA expression, with onset of this correlation preceding significant elevations in serum Pi. Despite these data suggesting that liver Pi influences liver hepcidin production, our finding might indicate that increased extrarenal Pi accumulation provides a reservoir for storing excess Pi until tissue accumulation achieves saturation, in which case the serum Pi compartment then gradually rises, resulting in hyperphosphatemia. Furthermore, our data suggest that prolonged exposure to Pi, if not maintained in adequate quantities, might trigger pathologic outcomes, as mice on 3% Pi show a noticeable degree of hypoferremia. None of the observed effects of the high Pi diet were mediated by FGFR4, as Fgfr4^−/− mice were comparable to wild-type mice in all the parameters measured. However, this work cannot exclude the potential of alternative FGFR isoforms which might mediate the effects of excess FGF23 toward functional iron deficiency following either adenine or 3% Pi diet, as a previous report exhibits the utilization of a single intraperitoneal injection of FGF23 blocking peptide was sufficient to rescue anemia (Agoro et al., 2018).

Excess dietary Pi was shown to directly exacerbate intestinal inflammation in a model of experimental colitis (Sugihara et al., 2017) and that reducing dietary Pi provides beneficial outcomes toward systemic inflammation, accelerated aging, and survival, as demonstrated in a model of senescence (Morishita et al., 2001). We likewise observed increased inflammation in our hyperphosphatemic mouse models. Inflammatory cytokines can directly target skeletal muscle cells to induce muscle wasting by increasing myostatin production (Zhang et al., 2013), which both together, enhances protein degradation and reduces protein synthesis, as CKD illustrates catabolic conditions which are attributable to the vicious cycle generated between mineral dyshomeostasis and inflammation (Czaya and Faul, 2019b). We indeed observed skeletal muscle wasting in adenine-induced CKD, high phosphate diet, and genetic model of CKD. Ablation of FGFR4 in mice did not improve skeletal muscle function following adenine or 3% Pi diets, suggesting hyperphosphatemia rather than pathologic FGF23-FGFR4 signaling might be the cause of skeletal muscle abnormalities (Figure 3). This hypothesis is supported by reports demonstrating excess Pi influences skeletal muscle dysfunction (Acevedo et al., 2016; Chen et al., 2018; Chung et al., 2020), although it is possible additional FGFR isoforms directly promote skeletal muscle wasting due to excess FGF23 following adenine or high Pi diet. However, a recent report suggests that FGF23 does not directly affect skeletal muscle dysfunction (Avin et al., 2018).

To assess whether reducing hyperphosphatemia can improve inflammation, anemia, and skeletal muscle wasting, we exposed Alport mice, a genetic model of progressive CKD, to a low Pi diet treatment. Indeed, despite severe elevations in serum FGF23, dietary Pi restriction limited functional iron deficiency (Figure 4). Our data also show liver Pi levels were reduced in Alport mice following low Pi diet treatment, in comparison to Alport mice on normal diet. These findings provide strong evidence that hyperphosphatemia, specifically pathologic liver Pi accumulation, rather than pathologic FGF23-FGFR4 signaling, might exacerbate inflammation and hypoferremia. Skeletal muscle function and mass were also improved by a low Pi diet in Alport mice, along with decreased expression of muscle myostatin and atrophy-related gene programs, culminating in larger myofiber size. These findings suggest the contribution of hyperphosphatemia to skeletal muscle wasting may result from an indirect mechanism that regulates inflammatory cytokines and their pleotropic activities, such as increased liver-derived IL1β and IL6, which might increase overall systemic levels that effectively target skeletal muscle. Despite this postulate, further work will be needed to determine if high extracellular Pi directly targets skeletal muscle cells to affect muscle function. Nonetheless, these data add to the growing list of adverse outcomes of Pi toxicity such as gingivitis, accelerated aging, vascular calcification and tumorigenesis (Erem and Razzaque, 2018). Furthermore, Alport mice on low Pi diet treatment displayed a reduced degree of pathologic kidney function, alterations in kidney morphology, and macroscopic parameters (Figure 4, Figure 4—figure supplement 1, Table 3). Thus, we cannot exclude that these beneficial outcomes in Alport mice observed on treatment may be a repercussion of slightly improved kidney function, as a recent report demonstrates elevated Pi concentrations directly affect proximal tubular function (Shiizaki et al., 2021).

Importantly, we identify a molecular mechanism that potentially links hyperphosphatemia to anemia and skeletal muscle dysfunction. Utilizing mouse primary hepatocytes, we demonstrate high extracellular Pi activates NFκB signaling and leads to subsequent inflammatory cytokine and hepcidin production (Figure 6). Employing PFA, a compound reported to reduce calcium–Pi deposition and cluster formation, as aggregates are a byproduct of increased extracellular Pi (Villa-Bellosta et al., 2007; Villa-Bellosta and Sorribas, 2009), we confirm NFκB activation is a direct action of Pi targeting hepatocytes, which prompts subsequent Slc20a1 mRNA expression, as observed from our BAY 11-7082 findings. This high extracellular Pi-NFκB signaling axis is observed in other reservoirs such as vascular smooth muscle cells and ex vivo kidney slices, as well as adjuncts the rewiring of various signaling networks that control cellular homeostasis following excessive Pi exposure (He et al., 2021; Rodríguez-Ortiz et al., 2020; Voelkl et al., 2018; Zhao et al., 2011). Although this reaffirms NFκB directly influences PiT-1 levels (Koumakis et al., 2019), it does not identify if our observations are dependent or independent of Pi translocation, as extracellular Pi might associate with various PiT-1 extracellular regions to influence PiT-1/PiT-1 homodimerization, PiT-1/PiT-2 heterodimerization or a conformational change in PiT-1 to initiate the activation of selected binding partners which mediate downstream signaling events (Bon et al., 2018; Forand et al., 2016). In addition to the amplified hepatic PiT-1 abundance and recognition of NFκB as a necessary mediator of high extracellular Pi in hepatocytes, we show that the effect of Pi on hepcidin requires the indirect actions of NFκB and biological activities of endogenous IL1β and IL6 proteins secreted by hepatocytes, as elucidated by our cell-based neutralization assay of these targeted cytokines (Figure 7). Based on these findings, we speculate increased liver Pi deposits might underlie a clinical association between elevated body Pi and inflammation, where the prolonged duration of tissue accumulation permits Pi in the liver to directly target hepatocytes to induce inflammatory gene programs and hepcidin expression, contributing to hypoferremia. This could explain associations of inflammation and anemia in FTC patients, in addition to patients with and without CKD, before they exhibit hyperphosphatemia (Ramnitz et al., 2016; Tran et al., 2016; Wojcicki, 2013).

Our study has some limitations. Although we confirm hyperphosphatemia affects specific complications, our study does not specifically address the actions of certain aggregate byproducts formed by increased extracellular Pi. Nonetheless, this principal emphasis on elevations in plasma Pi concentrations will ultimately impact the formation of byproducts. Notably, the identification of the specific Pi sensor which mediates our observed hepatic Pi actions are not definite and remains to be defined with our ongoing studies. Moreover, our study does not address the specific actions of hyperphosphatemia on bone metabolism. As bone is a reservoir of extracellular Pi, potential alterations in bone health could relay a crosstalk between bone, liver, and/or skeletal muscle, which might contribute to our reported observations.

In summary, we investigated whether hyperphosphatemia and/or pathologic FGF23-FGFR4 signaling aggravates inflammation, anemia, and skeletal muscle wasting. We establish hyperphosphatemia, as found in dietary Pi overload or in CKD, is a detrimental trigger which activates hepatic NFκB signaling to stimulate an inflammatory response, which in turn, exacerbates hypoferremia and widespread complications such as skeletal muscle wasting. Notably, these findings are independent of pathologic FGF23-FGFR4 signaling. Clinical studies have demonstrated conflicting outcomes with traditional Pi binders in individuals with nondialysis-dependent CKD, but modern Pi binders, such as ferric citrate, demonstrate greater efficacy (Francis et al., 2019; Toussaint et al., 2020), and are being evaluated for their effect on CKD comorbidities. Furthermore, reports assessing dietary Pi restriction in animal models are scarce. Our current experimental data suggest hyperphosphatemia, in itself, is pathologic and demands further attention for alternative strategies to resolve current ineffective approaches. Treatments, such as pharmacologic inhibition of type II Na/Pi cotransporters, hold potential for therapeutic actions (Clerin et al., 2020; Thomas et al., 2019) but do not aim at altered mineral metabolism. Using in vitro studies and complementary animal models, we provide insights regarding the interconnection between altered mineral metabolism and common complications. Dietary Pi restriction might alleviate these sequelae, if sustained effectively as a clinical treatment. By elucidating direct inflammatory actions of high extracellular Pi on hepatocytes, we expose additional adverse outcomes of hyperphosphatemia, besides vascular calcification. These findings may yield new targets for therapeutic development, with emphasis on hepatic Pi actions. Moreover, as studies indicate anti-FGFR4 therapy may be beneficial toward cardiomyopathy (Grabner et al., 2015), our data suggest these same beneficial outcomes for inflammation, anemia, and skeletal muscle wasting would not apply. Altogether, our study features a possibility to improve CKD patient survival and specific rare genetic disorders, such as FTC, by limiting excess body Pi.

All data generated and analyzed during this study are available through Dryad.

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Author details

1. Brian Czaya

   1. Division of Nephrology and Hypertension, Department of Medicine, The University of Alabama at Birmingham, Birmingham, United States
   2. Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7888-2432

2. Kylie Heitman

   Division of Nephrology and Hypertension, Department of Medicine, The University of Alabama at Birmingham, Birmingham, United States

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5345-2727

3. Isaac Campos

   Division of Nephrology and Hypertension, Department of Medicine, The University of Alabama at Birmingham, Birmingham, United States

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

4. Christopher Yanucil

   Division of Nephrology and Hypertension, Department of Medicine, The University of Alabama at Birmingham, Birmingham, United States

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

5. Dominik Kentrup

   Division of Nephrology and Hypertension, Department of Medicine, The University of Alabama at Birmingham, Birmingham, United States

   Contribution

   Formal analysis, Methodology

   Competing interests

   No competing interests declared

6. David Westbrook

   Division of Nephrology and Hypertension, Department of Medicine, The University of Alabama at Birmingham, Birmingham, United States

   Contribution

   Project administration

   Competing interests

   No competing interests declared

7. Orlando Gutierrez

   Division of Nephrology and Hypertension, Department of Medicine, The University of Alabama at Birmingham, Birmingham, United States

   Contribution

   Conceptualization

   Competing interests

   has received honoraria and grant support from Akebia and Amgen, grant support from GSK, honoraria from Ardelyx, Reata, and AstraZeneca, and serves on the Data Monitoring Committee for QED

8. Jodie L Babitt

   Division of Nephrology, Program in Membrane Biology, Massachusetts General Hospital, Harvard Medical School, Boston, United States

   Contribution

   Conceptualization, Methodology

   Competing interests

   has ownership interest in Ferrumax Pharmaceuticals and has been a consultant for Incyte Corporation, and Alnylam Pharmaceuticals

9. Grace Jung

   Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, United States

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

10. Isidro B Salusky

    Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, United States

    Contribution

    Conceptualization, Investigation

    Competing interests

    No competing interests declared

11. Mark Hanudel

    Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, United States

    Contribution

    Conceptualization, Investigation, Methodology

    Competing interests

    No competing interests declared

12. Christian Faul

    Division of Nephrology and Hypertension, Department of Medicine, The University of Alabama at Birmingham, Birmingham, United States

    Contribution

    Conceptualization, Funding acquisition, Investigation, Project administration, Resources, Supervision, Writing – original draft

    For correspondence

    cfaul@uabmc.edu

    Competing interests

    has served as a consultant for Bayer and Calico Labs, and he is the founder and currently the CSO of a startup biotech company (Alpha Young LLC)

    "This ORCID iD identifies the author of this article:" 0000-0002-7512-0977

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