Hyperphosphatemia Contributes to Systemic Inflammation and Anemia in Chronic Kidney Disease - PROJECT SUMMARY
Chronic kidney disease (CKD) is a health epidemic that increases risk of death due to various comorbidities.
Alterations in mineral metabolism are a hallmark of advanced CKD, where hyperphosphatemia and the
associated increase in serum concentrations of fibroblast growth factor (FGF) 23 have been suspected to
directly contribute to tissue damage and mortality, but the underlying mechanisms are not fully understood. We
previously found that by targeting cardiac myocytes via FGF receptor (FGFR) 4, elevated FGF23 activates a
specific signaling pathway and induces cardiac hypertrophy in rodent models of CKD. We also reported that by
activating this mechanism, FGF23 can directly target hepatocytes. However, the consequences of FGF23’s
hepatic action have not been investigated in vivo. Compared to FGF23, much less is known about the direct
pathologic actions of elevated serum phosphate. Mechanistic studies have shown that by targeting vascular
smooth muscle cells via specific phosphate transporters and signal mediators, elevated phosphate can cause
vascular calcification. Direct actions of elevated phosphate concentrations on the heart are not understood,
and potential effects of phosphate on the liver have not been analyzed so far. Our preliminary in vitro studies in
primary mouse hepatocytes indicate that phosphate and FGF23 can both induce the expression of
inflammatory cytokines, such as interleukin 6 (IL6), and of hepcidin. In Aim 1 we will characterize the
mechanism that mediates the phosphate effect on hepatocytes in vitro, and we will study whether phosphate
communicates with FGF23/FGFR4 signaling when stimulating IL6 and hepcidin production. Since IL6 is a
potent inducer of skeletal muscle atrophy and hepcidin causes functional iron deficiency, we will also
determine whether by targeting the liver, elevated serum levels of phosphate and FGF23 contribute to muscle
wasting and anemia. To study the contribution of FGF23 in this context, we have generated a novel mouse
model with hepatocyte-specific deletion of FGFR4. In Aim 2, we will determine whether following the induction
of kidney injury via administration of an adenine-supplemented diet, these mice are protected from increases in
hepatic and systemic levels of IL6 and hepcidin, as well as skeletal muscle injury and anemia. In the Col4a3
knockout model of CKD, we will inject a FGFR4-specific blocking antibody to determine if systemic FGFR4
inhibition has similar protective effects, which would suggest a therapeutic potential for anti-FGFR4 in CKD. In
our preliminary studies we also found that increasing phosphate concentrations induce FGF23 production in
cultured hepatocytes, and that mouse models of CKD as well as mice on high-phosphate diet express FGF23
in the liver, which is not detected in control mice. In Aim 3, we will test whether liver-derived FGF23 is required
for the in vivo effects of phosphate. We have generated a novel mouse model for the hepatocyte-specific
deletion of FGF23, and after administration of an adenine or high-phosphate diet, we will study if IL6 and
hepcidin production are reduced as well as potential protective effects on skeletal muscle and iron metabolism.
