Year: 2019
Type: article
Abstract: In chronic kidney disease (CKD), elevated serum levels of the phosphate regulating hormone fibroblast growth factor (FGF) 23 have emerged as powerful risk factors for cardiovascular disease and death. Mechanistically, FGF23 can bind and activate fibroblast growth factor receptor (FGFR) 4 independently of α-klotho, the canonical co-receptor for FGF23 in the kidney, which stimulates left ventricular hypertrophy and hepatic production of inflammatory cytokines. FGF23 has also been shown to independently predict progression of renal disease, however, whether FGF23 and FGFR4 also contribute to CKD remains unknown. Here, we generated a mouse model with dual deletions of FGFR4 and α-klotho, and we induced CKD in mice with either global deletion or constitutive activation of FGFR4. We demonstrate that FGF23 is not capable of inducing phosphaturia via FGFR4 and that FGFR4 does not promote or mitigate renal injury in animal models of CKD. Taken together our results suggest FGFR4 inhibition as a safe alternative strategy to target cardiovascular disease and chronic inflammation in patients with CKD without interrupting the necessary phosphaturic effects of FGF23.
Source: Scientific Reports
Authors: Ashlee Taylor, Christopher Yanucil, John Musgrove, Melody Shi, Shintaro Ide, Tomokazu Souma, Christian Faul, Myles Wolf, Alexander Grabner
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,790
Awards: Role of FGF23 in Mineral Metabolism Across the Spectrum of Chronic Kidney Disease, Activation of Cardiac FGFR4 Causes Left Ventricular Hypertrophy, Changes in phosphate metabolism cause pathologic cardiac remodeling in chronic kidney disease (CKD), G581683526, Vitamin D and soluble Klotho inhibit FGF23-mediated cardiac hypertrophy in Chronic Kidney Disease, G6686047177, G7855839706, G7882518124, G8881845922, UAB Diabetes Research Center
OpenAlex ID: W2978873988