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Kidney Week

Abstract: TH-PO736

FGFR4 Is Not Required for the Development of Cardiac and Renal Hypertrophy in Pregnancy

Session Information

Category: Women’s Health and Kidney Diseases

  • 2000 Women’s Health and Kidney Diseases

Authors

  • Richter, Beatrice, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Czaya, Brian A., University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Yanucil, Christopher, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Campos, Isaac D., University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Kentrup, Dominik, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Heitman, Kylie, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Faul, Christian, University of Alabama at Birmingham, Birmingham, Alabama, United States
Background

Pregnant women develop cardiac and renal hypertrophy as an adaption to increased blood volume, which is reversible without causing organ injury. Fibroblast growth factor (FGF) 23 is a bone-derived hormone that increases phosphate excretion by targeting the kidney via FGF receptor (FGFR) 1 and klotho. In chronic kidney disease, high FGF23 levels are associated with cardiovascular injury and can directly induce cardiac hypertrophy. FGF23 binds to FGFR4 on cardiac myocytes in a klotho-independent manner, thereby activating pro-hypertrophic signaling. In injured kidneys, FGF23/FGFR4 signaling promotes fibrosis. Here, we investigated whether FGF23/FGFR4 signaling contributes to cardiac and renal hypertrophy during pregnancy.

Methods

Virgin female C57BL/6J wildtype (WT), FGFR4 knockout (KO), and FGFR4-385R/R knockin (KI) mice were mated with proven male breeders. After 24 hours, males were removed, and females were sacrificed after 18 days in late pregnancy (LP). Age-matched, non-pregnant (NP) females served as controls. Heart and kidney mass and serum levels of FGF23, phosphate and calcium were determined. Heart and kidney tissue were further analyzed by qPCR.

Results

WT and KO mice develop cardiac and renal hypertrophy in LP, indicated by increased heart weight/tibia length and kidney weight/tibia length ratios when compared to respective NP controls. This effect is not observed in pregnant KI mice. Serum FGF23 increases in LP in all three genotypes. In WT-LP mice, serum calcium levels increase, while serum phosphate is unchanged when compared to WT-NP controls. Furthermore, cardiac Fgfr1 mRNA levels are reduced, and Fgf23 and Fgfr4 increased. In the kidney, Fgf23, Fgfr1, Fgfr4 and NaPi2c mRNA levels are unchanged, while NaPi2a is decreased, and klotho and Pit2 are elevated.

Conclusion

In LP, mice develop cardiac and renal hypertrophy and have elevated serum FGF23 levels. However, in this context FGFR4 does not seem to be required for the development of organ hypertrophy. Surprisingly, we found that activation of FGFR4 inhibits organ hypertrophy suggesting anti-hypertrophic actions of FGF23/FGFR4 signaling in pregnancy, which requires further mechanistic studies.

Funding

  • Other NIH Support