Abstract: PO1640
Mapping the Genetic Susceptibility of HIV-Associated Nephropathy in a Mouse Model
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - 2
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Steers, Nicholas J., Columbia University Irving Medical Center, New York, New York, United States
- Gupta, Yask, Columbia University Irving Medical Center, New York, New York, United States
- Lim, Tze Yin, Columbia University Irving Medical Center, New York, New York, United States
- Mo, Anna, Columbia University Irving Medical Center, New York, New York, United States
- Liang, Judy, Columbia University Irving Medical Center, New York, New York, United States
- Stevens, Kelsey O., Columbia University Irving Medical Center, New York, New York, United States
- D'Agati, Vivette D., Columbia University Vagelos College of Physicians and Surgeons, New York, New York, United States
- Sanna-Cherchi, Simone, Columbia University Irving Medical Center, New York, New York, United States
- Gharavi, Ali G., Columbia University Irving Medical Center, New York, New York, United States
Background
We studied the genetic determinants of nephropathy in HIV-1 transgenic (Tg) mice, a model that displays all 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 20 different inbred strains of mice to generate F1 hybrids. At 8 weeks of age, we evaluated the severity of nephropathy by histology, BUN, and proteinuria, hematuria and NGAL was analyzed in the urine. To map loci predisposing to HIVAN, we performed a GWAS using a mixed linear model method.
Results
Six strains (A/J, C3H/HeJ, DBA/1J, KK/HIJ , WSB/EiJ , and LP/J) were highly sensitive to the Tg resulting in severe glomerulosclerosis, 9 strains (129S1/SvImJ, Balb/CJ, C57BL/6J, C57BL/6NJ, C57BL/10J, C57L/J, C58/J, CAST/EiJ and NZB/BINJ) were resistant to the Tg resulting in limited to no glomerulosclerosis, and 5 strains were (CBA/J, DBA/2J, NOD/ShiLtJ, NZO/HlLtJ and FVB/NJ) had intermediate glomerulosclerosis. The glomerulosclerosis score correlated with the presence of casts, interstitial fibrosis and tubular atrophy, interstitial inflammation, proteinuria, elevated plasma BUN, and the detection of urine NGAL. A GWAS searching for haplotype distribution patterns that matched the high/low strain susceptibility pattern identified a genome-wide signal on Chr 13 within a previously known QTL for HIVAN. The interval contains Ssbp2, encoding a DNA binding protein that stabilizes transcriptional complexes by prevent proteasomal degradation. Ssbp2 is highly expressed in podocytes.
Conclusion
Our data demonstrates differences in the susceptibility of inbred strains to the HIV-1 transgene and suggest Ssbp2 as culprit in producing susceptibility to HIVAN in the mouse. Future studies will evaluate the role of Ssbp2 in vitro and in Ssbp2 null mice.
Funding
- Other U.S. Government Support