Get started
Work

Inhibition of FGFR signaling attenuates phosphaturia and early kidney injury in sickle cell disease mice

Year: 2026
Type: article
Abstract: We examined whether short term treatment with the pan-FGF Receptor (FGFR) inhibitor BGJ398 (Infigratinib) modulated impaired FGFR downstream signaling, phosphate wasting and markers of kidney damage in sickle cell disease (SCD) mice. Healthy control (Ctrl) and SCD mice were subcutaneously injected with BGJ398 for 24 h. In serum both FGF23 intact and carboxy-terminal-fragment FGF23 were significantly higher in SCD and were not decreased with BGJ398. In SCD mice, serum phosphate level was significantly decreased, and urine phosphate/creatinine ratio were significantly higher and BGJ398 significantly reduced urine phosphate wasting. Immunohistochemistry analysis of kidneys revealed that phosphate transporters NPT2a and PIT-2 proteins were significantly decreased in SCD kidneys and were significantly improved by BGJ398. Signaling molecules that mediate decreased NPT2a, and PIT-2 expression were significantly increased and were significantly reduced by BGJ398. Markers of SCD kidney injury such as glomeruli sclerosis, tubular-damage-marker NGAL, early kidney-damage-marker KIM1, inflammatory M1 iNOS + macrophages, and cytokines tumor necrosis factor alpha (TNFa) and interleukin-6 (IL-6) were significantly increased. BGJ398 did not reduce glomerular sclerosis or NGAL, but significantly reduced iNOS + macrophages, KIM-1, TNFa, and IL-6 in SCD kidneys. BGJ398 also significantly decreased kidney osteopontin and its receptor integrin αVβ3, that are associated with inflammation. In summary impaired FGFR downstream signaling mediated phosphaturia in SCD that could be modulated by BGJ398. We further suggest that osteopontin and aberrant integrin signaling contributes to kidney inflammation that can be partially rescued by BGJ398.
DOI: 10.1016/j.bbrep.2026.102671
Institution: UConn Health
Language: English
Field: Medicine
Open Access status: gold
Estimated APC paid: $2,700
OpenAlex ID: W7164479372
FWCI:
Cites: 36
Cited by:
Related to: 10