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Abstract: FR-PO689

Lisinopril-Mediated ACE Inhibition Reduces Proteinuria and Sclerosis in the G1/G1 but not the G2/G2 APOL1 Mouse Model of FSGS

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Sula Karreci, Esilida, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Zsengeller, Zsuzsanna Kinga, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Friedman, David, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Alper, Seth L., Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Pollak, Martin, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
Background

APOL1 gene variants G1 and G2 account for the 3 to 4-fold elevated risk of kidney disease in individuals of recent African ancestry. These variants confer protection against Trypanosomal disease, but individuals with two high-risk alleles are at higher risk of developing FSGS and renal failure. Molecular disease mechanisms remain controversial and targeted treatments for APOL1 kidney disease remain an unmet need.

Methods

Our lab has created APOL1 BAC transgenic mice that develop proteinuria and glomerulosclerosis upon injection of pCpG-free plasmid DNA encoding murine IFNg. After injection of G1/G1 and G2/G2 mouse groups with IFNg plasmid, mice were randomized on post-injection day 7 (after confirming proteinuria) to treatment with Lisinopril in the drinking water at 75 mg/L or to a no drug control group. Urinary albumin/creatinine ratio was measured biweekly. At time of sacrifice, kidney tissue was harvested, paraffin-embedded, and 4µm sections were stained with periodic acid-Schiff (PAS) stain. An FSGS score was computed from 30 glomeruli per mouse, each scored in a blind manner as normal or displaying segmental or global sclerosis.

Results

Treatment with the ACE inhibitor lisinopril reduced proteinuria by ~100-fold in APOL1 G1/G1 BAC-transgenic mice and greatly reduced severity of FSGS by histological criteria. In contrast, lisinopril treatment of G2/G2 mice produced improvement neither in proteinuria nor in the likelihood of developing severe FSGS in G2/G2 mice.

Conclusion

Lisinopril-mediated inhibition of ACE modified disease phenotype in the BAC-transgenic APOL1 G1/G1 mouse model of FSGS, but not in the G2/G2 model. These findings add to our understanding of APOL1 disease mechanisms in mouse models of FSGS and may provide insight into APOL1-associated human kidney disease. Early genotyping should in future allow trials of inhibition of the renin-angiotensin-aldosterone system starting before clinical onset of glomerular disease in patients with high-risk APOL1 alleles.

Funding

  • Other U.S. Government Support