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Abstract: FR-PO171

GDF-15/GFRAL Axis, Survival, and Kidney Protection in Lipopolysaccharide and Folic Acid Nephropathy in Mice

Session Information

  • AKI: Mechanisms - II
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Frikke-Schmidt, Henriette, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Meng, Rong, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Ho, George, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Farrington, Krista P., Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Pocai, Alessandro, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Mullican, Shannon, Janssen Research and Development LLC, Spring House, Pennsylvania, United States

Group or Team Name

  • Cardiovascular, Metabolism and Retina Therapeutic Area, Janssen Research & Development
Background

GFRAL, the receptor for Growth/differentiation factor-15 (GDF-15), is expressed only in the hindbrain and while this axis regulates food intake, the role of GFRAL in described reno-protective effects of GDF-15 is not well understood. Overexpression of GDF-15 has been shown to protect against lipopolysaccharide (LPS) induced acute kidney injury and mortality in mice, but it is not confirmed if this is mediated through GFRAL. To explore this, we assessed survival and kidney injury in GDF-15 overexpressing (hNAG-1 mouse line generated by Prof. Thomas Eling) or GFRAL deleted (GFRAL-/-) mice challenged with LPS or folic acid (FA)

Methods

hNAG-1 mice and wild type (WT) controls were given 12 mg/kg of intraperitoneal (IP) LPS and monitored for survival. Acute kidney damage was induced in GFRAL-/- mice and WT controls by IP administration of LPS (200 ug for survival, 250 ug for kidney function) or FA (250 mg/kg) and monitored for survival, plasma creatinine (pCre), blood urea nitrogen (BUN) and proteinuria.

Results

Survival: 72 hours after LPS, 86% of hNAG-1 mice were alive compared to only 39% of WT (p=0.0071 Log-rank test). LPS treated GFRAL-/- mice did not show significantly different survival versus WT controls (47% vs 79%, no significant difference Log-rank test). 7 days after FA administration, only 33% of the GFRAL-/- mice survived compared to 78% of WT mice (p=0.0146 Log-rank test).
Kidney function: 24 hours after LPS plasma pCre in the GFRAL-/- mice was increased versus WT controls (0.41±0.166 vs 0.27±0.080 mg/dl, p=0.0094 unpaired t-test) whereas BUN remained unchanged (129±12.8 vs 120±15.7 mg/dl). 7 days after FA only 33% of the GFRAL-/- mice survived compared to 78% in WT mice (p=0.0146 Log-rank test). On day 2 after FA (before any deaths occurred) GFRAL-/- mice had highly elevated proteinuria (2224±2508 vs 42.6±21.9 μg/mg urine albumin creatinine ratio, p=0.0046 unpaired t-test), whereas levels of plasma pCre (8.0±3.1 vs 5.8±4.7 mg/dl) and BUN did not change (42±24 vs 53±29mg/dl).

Conclusion

We confirm that GDF-15 overexpression improves survival in LPS challenged mice and show that lack of GFRAL augments LPS and FA induced kidney damage. Our data supports the involvement of GFRAL signaling in the observed reno-protective effect.

Funding

  • Commercial Support