Abstract: TH-PO229

Lysophosphatidic Acid Regulates FGF23 via LPAR1 in Response to AKI

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Simic, Petra, Massachusetts General Hospital , Brookline, Massachusetts, United States
  • Kim, Wondong, Massachusetts General Hospital , Brookline, Massachusetts, United States
  • Divieti Pajevic, Paola, Boston University, School of Dental Medicine, Boston, Massachusetts, United States
  • Tager, Andrew M., Harvard Medical School, Boston, Massachusetts, United States
  • Jüppner, Harald, Massachusetts General Hospital , Brookline, Massachusetts, United States
  • Wein, Marc N, MGH Endocrine Unit, Boston, Massachusetts, United States
  • Rhee, Eugene P., Massachusetts General Hospital , Brookline, Massachusetts, United States
Background

Lysophosphatidic acid (LPA) is one of the simplest phospholipids with a range of signaling actions throughout the body. It has been implicated as an important cofactor for calcitriol’s effect on osteoblast differentiation in vitro, and LPA receptor 1 knock-out (Lpar1-/-) mice are known to have osteoporosis.

Methods

As FGF23 is a predominantly bone-derived hormone modulated by calcitriol, we have tested the effect of LPA on FGF23 production in vivo in C57Bl6 and Lpar1-/- mice and in vitro in a conditionally immortalized osteocyte cell line (Ocy454 cells).

Results

Exogenous LPA (50 mg/kg i.p. single dose) stimulated intact and C-terminal FGF23 production 2.4 fold in C57Bl6 mice as compared to vehicle treated mice (n=8 per group) at 24 hours (P=0.02). This effect was corroborated in Ocy454 cells, with a 10 fold increase in C-terminal and intact FGF23 protein levels 24 hrs following LPA treatment (P=0.05); this effect was specifically dependent on the LPAR1 receptor, as the effect of LPA on FGF23 was abolished in CRISPR generated Lpar1-/- Ocy454 cells but not in Lpar4-/- cells (the other major LPA receptor expressed in osteocytes). Next, we tested in vivo whether the effect of LPA on FGF23 is dependent on LPAR1, injecting Lpar1-/- mice or WT littermates with a single dose of LPA (50 mg/kg i.p.) or vehicle (n=8 per group). LPA increased serum FGF23 levels in WT, but not in Lpar1-/- mice (1215 ± 200 pg/ml vs. 664 ± 98 pg/ml, respectively, P=0.01) after 24 hrs. Finally, we subjected Lpar1-/- mice or WT littermates (n=4 per group) to AKI by performing 35 minutes of bilateral ischemia reperfusion injury (IRI). Circulating levels of FGF23 were 1.5 fold greater in WT mice as compared to Lpar1-/- mice following IRI (P=0.04).

Conclusion

In summary, LPA stimulates FGF23 production in vitro and in vivo via the LPAR1 receptor and the effects of AKI on FGF23 are attenuated in LPAR1 deficient mice.

Funding

  • NIDDK Support