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Abstract: TH-PO514

FGF23 Does Not Induce Left Ventricular Hypertrophy in Female Mice with CKD

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Gerber, Claire, Northwestern University, Chicago, Illinois, United States
  • Chonira, Vikas, Northwestern University, Chicago, Illinois, United States
  • Wang, Xueyan, Northwestern University, Chicago, Illinois, United States
  • Capella, Maralee, Northwestern University, Chicago, Illinois, United States
  • Courbon, Guillaume, Northwestern University, Chicago, Illinois, United States
  • David, Valentin, Northwestern University, Chicago, Illinois, United States
  • Martin, Aline, Northwestern University, Chicago, Illinois, United States
Background

Increased levels of fibroblast growth factor 23 (FGF23) in chronic kidney disease (CKD) are associated with development of left ventricular hypertrophy (LVH) and mortality. Men progress more rapidly to end stage renal disease and have an increased risk of cardiovascular death compared to women. We assessed whether delayed onset of CKD and/or delayed elevations of FGF23 levels in females could explain better cardiovascular outcomes than in males.

Methods

We studied B6 wild-type (WT) and Col4a3null male and female littermate mice with progressive CKD at 4, 8, 12, 16, and 20 weeks of age. At each time point, we analyzed parameters of kidney and heart morphology and function, and we measured serum FGF23 levels. In parallel, we assessed the lifespan in separate groups of mice.

Results

As previously described, Col4a3null males display impaired kidney function, increased serum FGF23 levels, development of LVH and reduced lifespan. Both Col4a3null males and females showed signs of proteinuria at 4 weeks (albumin to creatinine ratio (ACR); p<0.05 vs. sex- and age- matched WT). Progressive decline in kidney function resulted in increased levels of blood urea nitrogen (BUN) after 8 weeks of age in Col4a3null females, and only after 12 weeks in Col4a3null males (p<0.05 vs. sex- and age- matched WT). By 20 weeks, elevations of BUN, ACR and hypertension were similar in Col4a3null males and females. Serum FGF23 levels increased in both Col4a3null males and females after 8 weeks (p<0.05 vs. sex- and age- matched WT). Interestingly, Col4a3null females displayed higher FGF23 levels at all timepoints and steeper elevations of FGF23 levels during CKD progression than Col4a3null males, resulting in 50% higher FGF23 levels at 20 weeks (p<0.05 vs. Col4a3null males). Unlike Col4a3null males, and despite earlier onset of kidney disease and higher elevations of FGF23 levels, Col4a3null females did not develop LVH and lived 1.5 week longer than Col4a3null males in average.

Conclusion

In this well-established model of progressive CKD, absence of LVH in female mice may represent a survival advantage compared to males. The earlier onset of CKD and higher FGF23 levels in females suggest a role for female-specific cardioprotective mechanisms that remain to be determined.

Funding

  • NIDDK Support