Publication Date

2016-06-24

Availability

Open access

Embargo Period

2016-06-24

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Molecular Cell and Developmental Biology (Medicine)

Date of Defense

2016-05-30

First Committee Member

Christian Faul

Second Committee Member

Pedro Salas

Third Committee Member

Barry Hudson

Fourth Committee Member

Ramiro Verdun

Abstract

Chronic kidney disease (CKD) is a global health problem that affects 10-15% of the adult population worldwide and significantly increases the risk of death. Patients with CKD develop marked elevations in circulating levels of the phosphaturic hormone, fibroblast growth factor 23 (FGF23), which correlate with the stage of disease, and are associated with higher risk of mortality. Chronic inflammation is a hallmark of CKD. Circulating levels of inflammatory cytokines, such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) are significantly elevated in CKD patients and increase with disease progression. This inflammatory burden has been suggested to be a significant contributor to the high mortality rate in CKD. Furthermore, recent clinical studies have demonstrated that in CKD elevated serum levels of FGF23 are independently associated with higher circulating levels of inflammatory cytokines, which can stimulate FGF23 production in osteocytes. These correlative studies suggest a causative role of FGF23 in the development of systemic inflammation in CKD; however, the sources of inflammation and precise molecular mechanisms underlying the pathological interrelationship between deterioration of renal function, elevated FGF23 production and amplification of the inflammatory state are unknown. This thesis project explores the direct effects of FGF23 on the liver. Our data indicate that FGF23 can directly stimulate hepatocytes to produce inflammatory cytokines in the absence of α- klotho, which is the FGF23 co-receptor in the kidney that is not expressed by hepatocytes. By activating FGF receptor isoform 4 (FGFR4), FGF23 stimulates phospholipase Cγ (PLCγ)/calcineurin/nuclear factor of activated T cells (NFAT) signaling in hepatocytes, which increases expression and secretion of inflammatory cytokines, including CRP. We show that the elevation of serum FGF23 levels increases hepatic and circulating levels of CRP in wild-type mice, but not in FGFR4 knockout mice. Furthermore, administration of an isoform-specific FGFR4 blocking antibody reduces hepatic and circulating levels of CRP in the 5/6 nephrectomy rat model of CKD. By demonstrating that FGF23 can directly stimulate hepatic secretion of inflammatory cytokines, our findings suggest a novel mechanism of chronic inflammation in patients with CKD. We postulate that FGFR4 blockade might have therapeutic anti-inflammatory effects in CKD.

Keywords

Chronic Kidney Disease; FGF23; Inflammation; Liver; FGFR4

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