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Abstract: SA-OR056

APOL1 Risk Variants Affect Podocyte Lipid Homeostasis and Energy Production in FSGS

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Ge, Mengyuan, University of Miami School of Medicine, Miami, Florida, United States
  • Ducasa, Gloria Michelle, University of Miami School of Medicine, Miami, Florida, United States
  • Molina David, Judith T., University of Miami School of Medicine, Miami, Florida, United States
  • Hoek, Maarten, Merck & Company, Inc., Kennilworth, New Jersey, United States
  • Kopp, Jeffrey B., NIDDK, NIH, Bethesda, Maryland, United States
  • Fontanesi, Flavia, University of Miami School of Medicine, Miami, Florida, United States
  • Merscher, Sandra M., University of Miami School of Medicine, Miami, Florida, United States
  • Fornoni, Alessia, University of Miami School of Medicine, Miami, Florida, United States
Background

Focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder causing chronic kidney disease. Susceptibility to FSGS in African Americans is associated with the presence of genetic variants of the Apolipoprotein L 1 gene (APOL1) named G1 and G2. We recently published that mice with a podocyte-specific, doxycycline (Dox)-inducible expression of constitutively active NFATc1nuc (NFAT;Podocin-rtTA, DT) represent a valuable new model for FSGS.

Methods

Human urinary podocyte-like epithelial cells (HUPECs) carrying different APOL1 genetic variants were established from patients with FSGS and used for in vitro studies and human BAC transgenic mice expressing the APOL1 genetic variants (G0, G1 or G2) under the endogenous promoter for in vivo studies. DT mice were expanded for consecutive breeding to G0, G1 or G2 mice to generate triple transgenic mice (TT). NFATc1nuc transgene expression was induced by feeding of Dox chow (200 ppm) for 4 months.

Results

HUPECs carrying G1/G2 alleles are characterized by lipid droplet remodeling in association with decreased oxygen consumption, ATP generation and reduced mitochondrial membrane potential, while an increased abundance of super complexes was observed. In vivo, we tested the relative contribution of APOL1 risk variant expression to podocyte injury in APOL1 transgenic mice at baseline as well as in TT mice. Glomerular expression of APOL1 mRNA was similar among transgenic mice carrying APOL1 G0 and G1, but significantly lower in G2 carrying mice and these mice did not develop proteinuria at least up to 7 months of age (G2 mice were then excluded due to the low APOL1 mRNA levels). Meanwhile, TT mice carrying the G1 allele showed increased proteinuria, less body weight gain, higher serum BUN levels, more severe glomerulosclerosis and kidney cortex fibrosis when compared with G0 TT and their DT littermates. A strong correlation between serum BUN and kidney cortex cholesterol esters was observed.

Conclusion

Our data reveal that APOL1 risk variant expression may play a role in modulating lipid homeostasis and energy production in podocytes. APOL1 risk variant expression in mice does not impair kidney function at baseline whereas APOL1 G1 expression may contribute to APOL1 mediated susceptibility in NFAT-mediated FSGS.

Funding

  • NIDDK Support