Abstract: SA-PO328
APOL1 G1 Risk Variant Contributes to Podocyte Injury in a Mouse Model of FSGS
Session Information
- Cellular Crosstalk in Glomerular Diseases - II
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
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
- Hoek, Maarten, Merck & Co., Inc, Kenilworth, New Jersey, United States
- Kopp, Jeffrey B., NIDDK, NIH, Bethesda, Maryland, 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 podocyte-specific, doxycycline (Dox)-inducible expression of constitutively active NFATc1nuc (NFAT) represent a valuable new model for FSGS.
Methods
Human BAC transgenic mice that express the different APOL1 genetic variants (G0, G1, G2) under the endogenous promoter were used in this study. Podocyte specific Dox-inducible constitutively active NFATc1 mice (NFAT;Podocin-rtTA, DT) were expanded for consecutive breeding to G0, G1 or G2 BAC transgenic mice to generate triple transgenic mice (APOL1;NFAT;Podocin-rtTA, TT). NFATc1nuc transgene expression was induced by feeding of doxycycline chow (200 ppm) for 4 months. Urinary albumin-to-creatinine ratios were determined using mouse specific albumin ELISA and creatinine companion kits. Blood samples collected from mice at sacrifice were analyzed for BUN. Perfused kidneys were fixed and paraffin embedded for H&E, PAS staining.
Results
We tested the relative contribution of APOL1 risk variant expression to podocyte injury in mice expressing each of the APOL1 genetic variants under the control of the endogenous promoter region at baseline as well as in a mouse model of FSGS-like injury. Glomerular expression of APOL1 mRNA was similar among BAC transgenic mice carrying APOL1 G0 and G1, but significantly lower in G2 carrying mice (p<0.01) and these mice did not develop proteinuria for at least up to 7 months of age. Histological analysis among APOL1 transgenic mice carrying each of the APOL1 genetic variants and wildtype mice revealed no differences. However, Dox-induced TT mice carrying the G1 allele showed increased proteinuria, higher serum BUN levels and a more severe form of glomerulosclerosis when compared with induced TT mice carrying G0 or G2. Induced G1 TT mice were also characterized by an earlier onset of proteinuria which remained sustained over time.
Conclusion
Our data reveal that transgenic 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