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Abstract: TH-OR045

Lipocalin 2 Regulates FGF23 Production in CKD

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Courbon, Guillaume, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Francis, Connor, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Gerber, Claire, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Capella, Maralee, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Wang, Xueyan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Martin, Aline, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • David, Valentin, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

Production of fibroblast growth factor 23 (FGF23) is increased during chronic kidney disease (CKD) progression and associated with left ventricular hypertrophy (LVH), cardiac failure, and mortality. Lcn2, encoding a pro-inflammatory and iron-shuttling molecule, is the topmost expressed gene in the kidneys of the Col4a3KO mouse model of CKD. Serum Lcn2 and FGF23 levels are strongly correlated, suggesting that Lcn2 might control FGF23 production. Here, we investigated the role of Lcn2 in FGF23 regulation in health and CKD.

Methods

First, we injected WT mice with recombinant Lcn2 and measured serum FGF23 levels. Then, we crossed Lcn2KO mice with Col4a3KO (CKD) mice and analyzed the renal and cardiac functions of WT, Lcn2KO, CKD, and CKD/Lcn2KO littermates at 23 weeks of age. We next exposed WT and Lcn2KO mice to 3 established models of FGF23 induction: acute inflammation, a low iron diet or a high phosphate diet- to identify if Lcn2 mediates the increase in FGF23 in response to these stimuli. In addition, we tested whether Lcn2 directly controls Fgf23 transcription in osteoblast cultures.

Results

Administration of Lcn2 to healthy mice increased mRNA and serum FGF23 levels by 3-fold. As previously shown, mice with advanced CKD displayed impaired kidney function, increased levels of serum Lcn2, hyperphosphatemia, increased bone and serum FGF23, anemia, hypertension, LVH and reduced lifespan. Deletion of Lcn2 in CKD mice partially improved kidney function and prevented hypertension. Compared to CKD mice, CKD/Lcn2KO mice had normal levels of serum iron, ferritin and transferrin saturation. Importantly, CKD/Lcn2KO mice displayed 90% reductions in Fgf23 mRNA and serum FGF23 levels (p<0.05) and did not develop LVH. CKD/Lcn2KO mice lived significantly longer than CKD littermates (+6.7 weeks, i.e. +30%, p<0.05). As expected, serum FGF23 levels increased in WT mice in response to acute inflammation, low iron diet and high phosphate diet. Interestingly, Lcn2 deletion only prevented FGF23 elevations in response to acute inflammation. Finally, we showed that Lcn2 increased Fgf23 transcription in cultured osteoblasts and we identified cAMP / PKA signaling as a pathway mediating the stimulation of FGF23 by Lcn2.

Conclusion

Our results show that Lcn2 is an important regulator of FGF23 production in CKD that might mediate FGF23 response to inflammation.

Funding

  • NIDDK Support