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Abstract: TH-OR33

Role of miR-122 on FGF23 Cleavage

Session Information

Category: Bone and Mineral Metabolism

  • 501 Bone and Mineral Metabolism: Basic

Authors

  • Thomas, Jane Joy, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Von Drasek, John Charles, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Courbon, Guillaume, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Spindler, Jadeah Jeannine, 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

In chronic kidney disease (CKD), iron deficiency and inflammation contribute to elevated levels of intact fibroblast growth factor 23 (iFGF23) by increasing FGF23 production. Proteolytic cleavage of intact fibroblast growth factor 23 (iFGF23) yields C-terminal FGF23 peptides (Cter-FGF23) that play a protective role in iron deficiency anemia (IDA) and inflammation. O-glycosylation of iFGF23 cleavage site by GALNT3 protects iFGF23 from cleavage, but the regulation of GALNT3 is unknown.

We found that IDA increases the expression of miR-122-5p (miR122), which is a predicted inhibitor of Galnt3 expression. We hypothesized that inhibition of GALNT3 by miR122 results in increased iFGF23 cleavage in IDA.

Methods

Since miR122 is mainly produced by the liver, we generated mice harboring a conditional deletion of miR122 in hepatocytes (miR122cKO) by crossing miR122 floxed mice with mice expressing a Cre recombinase driven by the Albumin promoter. We induced IDA by feeding 3-week-old wild-type (WT) and miR122cKO mice either a control diet (Ctr) or a low iron diet (IDA) for 3 weeks. At 6 weeks of age, we analyzed serum biochemical and hematological parameters as well as bone Galnt3 expression in all mice.

Results

Compared to WT-Ctr, miR122cKO-Ctr mice exhibited reduced miR-122 levels, increased bone Galnt3 expression and iFGF23 levels, despite normal total cFGF23. These mice also showed reduced iron levels and transferrin saturation, but normal hemoglobin levels and red blood cells counts. As expected, WT-IDA mice were anemic and showed higher levels of miR122, reduced Galnt3 expression along with a 3.6-fold increase in total cFGF23 compared to WT-Ctr, and a slight but significant increase in iFGF23. Compared to WT-IDA, miR122cKO-IDA mice showed increased Galnt3 expression, total cFGF23 and iFGF23 levels, resulting in an increased i/cFGF23 ratio, a surrogate marker of FGF23 cleavage. miR122cKO-IDA mice also exhibited further reduced levels of iron and transferrin saturation, but this did not aggravate the severity of anemia in these mice.

Conclusion

Our results demonstrate that iron deficiency increases miR122, which inhibits osseous Galnt3 expression and results in increased FGF23 cleavage, elevated Cter-FGF23 but reduced iFGF23. miR122 could be a potential therapeutic target to reduce iFGF23 and thus improve adverse outcomes in early stages of CKD.

Funding

  • NIDDK Support