Soluble Urokinase Receptor Mediates Elevation of Fibroblast Growth Factor 23 (FGF-23)

Background: Soluble urokinase receptor (suPAR) is a circulating immune factor. Elevation of suPAR has been associated with acute or chronic kidney injuries in both patients and experimental models. Its implication in inflammation remains unclear Methods: We established a folic acid (FA) renal injury model in different mouse strains with different circulating suPAR levels, including full length or a secreted suPAR (msuPAR2) transgenic (Tg), wild type with regular suPAR, uPAR knockout without any suPAR. Samples were collected on day 1, 3, 7, and 14 after FA injection. Renal function was evaluated by BUN. Additional serum markers were tested for IL-6, KIM-1, Periostin, and FGF-23 levels. AlphaFold and PyMOL were performed to predict suPAR interacting partners. µCT scan was done to assess the effect of suPAR on bone mass Results: At baseline, µCT analysis indicates increased trabecular bone mass in msuPAR2-Tg mice specifically without changes of serum FGF23 or phosphate levels. 24 hours after FA injection, BUN was increased in all mice with highest levels seen in msuPAR2-Tg mice, while IL-6 and KIM-1 levels unremarkable across the strains. A distinct rise in serum FGF23 was observed only in msuPAR2-Tg mice on day 3. It declined by day 7 as kidney fibrosis developing, returned to baseline by day 14 when fibrosis aggravated. AlphaFold analysis suggests msuPAR2 dimer interacts with klotho, but not FGF23 or FGFR1, with high structural reliability (pLDDT >70, pTM >0.5). Key interacting residues serine, threonine, and tyrosine may serve as phosphorylation sites for kinase signaling Conclusion: Serum FGF23 was particularly elevated in FA-treated msuPAR2-Tg mice. Binding of msuPAR2 dimer to Klotho likely modulates FGF23 signaling in the kidney, with key suPAR residues serving as potential phosphorylation sites. As the increased FGF23 has been associated with different diseases including chronic kidney injury, targeting suPAR-klotho interaction could provide novel therapeutic insights. Further research is warranted to elucidate exactly how suPAR regulates FGF23 expression and it signaling pathway involved in the relevant kidney injuries Funding: NIDDK Support