All ETDs from UAB

Advisory Committee Chair

Christian Faul

Advisory Committee Members

Stefanie Krick

Bradley Yoder

Adam R Wende

Stijn De Langhe

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The fibroblast growth factor (FGF) family consists of a group of proteins whose diverse biological functions are mediated by receptor tyrosine kinases, termed FGF receptors (FGFR) 1-4. While paracrine FGFs require heparin sulfate as a co-factor for FGFR bind-ing and signaling, it has been assumed that endocrine FGFs, such as FGF23, do not bind heparin but instead require klotho, a family of transmembrane proteins, as a co-receptor on specific target cells. FGF23 acts as bone-derived hormone that targets tubular epitheli-al cells in the kidney via FGFR1 and α-klotho to reduce renal phosphate uptake. In chron-ic kidney disease (CKD), the kidney loses FGF23 responsiveness resulting in increased serum levels of phosphate and FGF23. Elevated FGF23 can activate FGFR4 in cells lack-ing α-klotho, such as cardiac myocytes, thereby contributing to cardiac injury, the leading cause of death in CKD. Here, we report that the soluble form of α-klotho (SKL), that is released from the kidney into the circulation, can bind FGF23 and specific FGFR isoforms thereby mediating FGF23 responsiveness in cells lacking klotho as well as in-hibiting FGFR4-induced FGF23 effects in cardiac myocytes. This mechanism, combined with our finding that SKL can block the binding of certain paracrine FGFs to FGFRs and thereby their mitogenic effects, might underlie the pleiotropic, tissue-protective effects of SKL. To test these effects in pre-clinical and clinical studies, we have developed novel assays to detect and quantify levels of SKL as well as to produce recombinant SKL pro-tein, which will help to identify animal models and patient populations with low SKL iv levels and provide bioactive SKL for therapeutic administration. Surprisingly, we also found that heparin acts as a FGF23 co-receptor by mediating FGF23 binding mainly to FGFR4 and thereby increases FGF23 effects on cardiac myocytes. Our study suggests that frequent heparin injections routinely done during the hemodialysis process, contrib-ute to cardiac injury and the high mortality in patients with end-stage kidney disease who have extremely high serum FGF23 levels. Our concern regarding the safety of a standard-of-care is supported by our studies in two animal models with elevated FGF23, where repetitive heparin injections significantly aggravate cardiac hypertrophy.

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