Hyperphosphatemia increases inflammation to exacerbate anemia and skeletal muscle wasting independently of FGF23-FGFR4 signaling

Abstract

Elevations in plasma phosphate concentrations (hyperphosphatemia) occur in chronic kidney disease (CKD), in certain genetic disorders, and following the intake of a phosphate-rich diet. Whether hyperphosphatemia and/or associated changes in metabolic regulators, including elevations of fibroblast growth factor 23 (FGF23) directly contribute to specific complications of CKD is uncertain. Here we report that similar to patients with CKD, mice with adenine-induced CKD develop inflammation, anemia and skeletal muscle wasting. These complications are also observed in mice fed high phosphate diet even without CKD. Ablation of pathologic FGF23-FGFR4 signaling did not protect mice on an increased phosphate diet or mice with adenine-induced CKD from these sequelae. However, low phosphate diet ameliorated anemia and skeletal muscle wasting in a genetic mouse model of CKD. Our mechanistic in vitro studies indicate that phosphate elevations induce inflammatory signaling and increase hepcidin expression in hepatocytes, a potential causative link between hyperphosphatemia, anemia and skeletal muscle dysfunction. Our study suggests that high phosphate intake, as caused by the consumption of processed food, may have harmful effects irrespective of pre-existing kidney injury, supporting not only the clinical utility of treating hyperphosphatemia in CKD patients but also arguing for limiting phosphate intake in healthy individuals.

The effect of high-dose vitamin D supplementation on hepcidin-25 and erythropoiesis in patients with chronic kidney disease

“…In regard to variables potentially reflecting a pro-inflammatory effect, S-phosphate, CRP, and S-FGF-23 increased within the treatment group, but not as compared to the PBO group, in which FGF23 also increased, raising questions regarding causality. Nevertheless, S-phosphate and S-FGF-23 are molecules that risk accumulation upon VD supplementation and both have potential direct, or indirect, pro-inflammatory effects which may be reflected by the increase over time in CRP, although a trend for increase in CRP ( p = 0,06) was observed in the PBO group too [ 81 , 82 ]. FGF-23 elevations constitute a potentially undesirable effect of VD supplementation for which CKD patients may be at particular risk [ 83 ].…”

Phosphate induces inflammation and exacerbates injury from cigarette smoke in the bronchial epithelium

“…For experiments involving adenine-induced kidney failure, a dietary timeline previously described was used 8 , 27 . Briefly, 10- to 14-week-old mice on a C57BL/6 background were placed on a customized diet containing 0.2% adenine (TD.140290, Envigo) for 6 weeks, switched to a customized diet containing 0.15% adenine (TD.170304, Envigo) for 2 weeks, then transitioned back to the 0.2% adenine diet for 6 more weeks.…”

“…Human bronchial epithelial cells (BEAS-2B, CRL-9609, ATCC) were cultured in Bronchial Epithelial Cell Growth Basal Medium (CC-3171, Lonza) with Bronchial Epithelial Cell Growth Medium SingleQuots Supplements and Growth Factors (CC-4175, Lonza) on tissue culture treated plates coated with collagen type IV (C7521, Sigma-Aldrich) as previously described 16 . Cells were treated with appropriate amounts of sodium phosphate (0.5 M; pH 7.4) and sodium sulfate (0.5 M; pH 7.4) buffers, prepared as previously described 8 , to produce final desired concentrations and incubated 24 h in a humidified 5% CO 2 incubator at 37 °C. Sodium sulfate served as a negative control in response to increased anion balance.…”

“…This hyperphosphatemia triggers elevations in fibroblast growth factor (FGF) 23 levels, a bone-derived hormone responsible for suppressing renal phosphate reabsorption 4 . Disruptions in this mineral homeostasis have been linked to cardiovascular 5 and bone disease 6 , hyperparathyroidism 7 , and anemia 8 , as well as renal failure from which these diseases can originate. However, there is limited research surrounding the consequences of CKD on lung function.…”

Phosphate Burden and Organ Dysfunction

“…P62 is a stress induced protein which leads to inclusion body formations and can also target ubiquitinated proteins for digestion ( Chung et al, 2020 ). Experimental animal studies have shown that hyperphosphatemia increases inflammation to intensify anemia and skeletal muscle wasting ( Czaya et al, 2022 ); phosphate burden induces hepatic levels of IL-6 and IL-1β to enhance the expression of hepcidin, a potential causative link between hyperphosphatemia, anemia, and skeletal muscle dysfunction ( Czaya et al, 2022 ). Hepcidin regulates systemic iron homeostasis by blocking intestinal iron absorption and macrophage iron recycling at high levels ( Czaya et al, 2022 ).…”