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Kidney Week

Abstract: FR-PO1019

Interstrain Variation in Severity of Nephropathy and Immunoglobulin Levels in HIV-1 Transgenic Mice

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

  • Steers, Nicholas J., Columbia University, New York, New York, United States
  • Na, Young-Ji, Columbia University, New York, New York, United States
  • Demaria, Natalia D., Columbia University, New York, New York, United States
  • Lam, Wan yee, Columbia University, New York, New York, United States
  • D'Agati, Vivette D., Columbia University College of Physicians and Surgeons, New York, New York, United States
  • Gharavi, Ali G., Columbia University, New York, New York, United States
Background

We studied the genetic and immunological determinants of nephropathy in HIV-1 transgenic (Tg) mice, a model that displays the clinical and molecular signatures of collapsing FSGS. On the FVB/NJ background over 80% of the Tg-FVB mice develop significant glomerulosclerosis; however F1 hybrids with other inbred strains of mice demonstrate variable penetrance from completely resistant to highly sensitive.

Methods

Tg-FVB mice were crossed with 12 different inbred strains of mice to generate F1 hybrids. At 8 weeks of age, we evaluated the severity of nephropathy by histology, analysis BUN, and serum IgA and IgG. Urine was analyzed for proteinuria, hematuria and NGAL.

Results

Three stains (A/J, C3H/HeJ, and DBA/1J) were highly sensitive to the Tg resulting in severe glomerulosclerosis, 4 strains (129S1/SvImJ, C57BL6/J, C57BL6/NJ, and CAST/EiJ) were resistant to the Tg resulting in limited to no glomerulosclerosis, and 5 strains (CBA/J, DBA/2J, NOD/ShiLtJ, NZO/HlLtJ and WSB/EiJ) had intermediate glomerulosclerosis. Preliminary analysis of the laboratory strains of mice indicated that the MHC haplotype b was associated with limited to no glomerulosclerosis. The glomerulosclerosis score correlated with the presence of casts, interstitial fibrosis and tubular atrophy, interstitial inflammation, proteinuria, elevated plasma BUN, and decreased plasma IgG concentrations. To determine if there were baseline differences between the 12 wildtype F1 hybrid mice, IgA, IgG and BUN plasma concentrations were determined. Significant differences were observed in the BUN (ANOVA p-value = 0.014), IgG (ANOVA p-value = 0.016), and highly significant differences were observed in plasma IgA (ANOVA p-value = 0.0022), between the groups of mice. No kidney pathologywas observed in the wildtype F1 hybrid mice.

Conclusion

Our data demonstrates differences in the immunoglobulin levels and BUN in the steady state of 12 different F1 wildtype strains of mice. The MHC b haplotype was associated with reduced penetrance of nephropathy. Future studies will include additional inbred stains of mice and GWAS analysis, to confirm findings and identify additional immunological and genetic influences.

Funding

  • Other U.S. Government Support