FGFR4 does not contribute to progression of chronic kidney disease

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.

Role of Klotho in Hyperglycemia: Its Levels and Effects on Fibroblast Growth Factor Receptors, Glycolysis, and Glomerular Filtration

“…Studies of the level and function of FGFRs in renal tissue in diabetic individuals are scarce. Consistent with the present findings, Taylor et al, reported a decrease in the protein level of FGFR4 in mice with CKD [37]. Cheng et al, reported a decrease in the expression of FGFRs in the kidneys in diabetic rats, which can be due to an increase in the presence of ADAM10/17 metalloproteinases, which have been recently proven to cleave FGFRs [38,39].…”

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

“…After the 14-week duration, mice were euthanized under 2.5% isoflurane anesthesia and samples were prepared as described below. This experimental timeline is in accordance with previous studies ( Noonan et al, 2020 ; Taylor et al, 2019 ). Adenine is known to induce kidney tubule-interstitial damage and is considered a dietary model of CKD.…”

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

“…After the 14-week duration, mice were euthanized under 2.5% isoflurane anesthesia and samples were prepared as described in supplemental materials and methods. This experimental timeline is in accordance with previous studies (Noonan et al, 2020;Taylor et al, 2019). Adenine is known to induce kidney tubuleinterstitial damage and is considered a dietary model of CKD.…”