Identification of the Nephropathy-Susceptibility Locus HIVAN4

Abstract

HIVAN1, HIVAN2, and HIVAN3 are nephropathy-susceptibility loci previously identified in the HIV-1 transgenic mouse, a model of collapsing glomerulopathy. The HIVAN1 and HIVAN2 loci modulate expression of Nphs2, which encodes podocin and several other podocyte-expressed genes. To identify additional loci predisposing to nephropathy, we performed a genome-wide scan in 165 backcross mice generated between the nephropathy-sensitive HIV-1-transgenic FVB/NJ (TgFVB) strain and the resistant Balb/cJ (BALB) strain. We identified a major susceptibility locus (HIVAN4) on chromosome 6 G3-F3, with BALB alleles conferring a twofold reduction in severity (peak LOD score ϭ 4.0). Similar to HIVAN1 and HIVAN2, HIVAN4 modulated expression of Nphs2, indicating a common pathway underlying these loci. We independently confirmed the HIVAN4 locus in a sister TgFVB colony that experienced a dramatic loss of nephropathy subsequent to a breeding bottleneck. In this low-penetrance line, 3% of the genome was admixed with BALB alleles, suggesting a remote contamination event. The admixture localized to discrete segments on chromosome 2 and at the HIVAN4 locus. HIVAN4 candidate genes include killer lectin-like receptor genes as well as A2m and Ptpro, whose gene products are enriched in the glomerulus and interact with HIV-1 proteins. In summary, these data identify HIVAN4 as a major quantitative trait locus for nephropathy and a transregulator of Nphs2. Furthermore, similar selective breeding strategies may help identify further susceptibility loci.

APOL1-G0protects podocytes in a mouse model of HIV-associated nephropathy

“…The Tg26/HIVAN4 mouse model of HIVAN is transgenic for a subgenomic HIV-1 provirus and spontaneously develops a progressive and lethal kidney disease that replicates most of the pathology and clinical presentation of the human disease. 26,27 F1 hybrids from intercrossing Tg26/HIVAN4 with Tg-G0 or Tg-G2 (dual transgenics referred to as "Tg26+G0" and "Tg26+G2") were examined at 200 days of age for pathology and renal function using parameters previously established to quantitate disease severity in the Tg26 model. 28 Age-matched non-transgenic (wildtype), Tg26/HIVAN4, and Tg-G0 and Tg-G2 single transgenics were also examined as comparators.…”

“…25 The Tg26/HIVAN4 mouse model of HIVAN is a congenic of Tg26 26 that develops less severe kidney disease and has been previously described. 27 The APOL1 transgenic are on the FVB/N background and the Tg26/HIVAN4 model is >99% FVB/N with a 60Mb BALB/c-derived genomic region referred to as the HIVAN4 locus. 27 The Tg26/HIVAN4 and APOL1 transgenic models are maintained as carriers (hemizygotes), thus the intercross generated all possible single and dual transgenics for age-matched comparisons.…”

“…27 The APOL1 transgenic are on the FVB/N background and the Tg26/HIVAN4 model is >99% FVB/N with a 60Mb BALB/c-derived genomic region referred to as the HIVAN4 locus. 27 The Tg26/HIVAN4 and APOL1 transgenic models are maintained as carriers (hemizygotes), thus the intercross generated all possible single and dual transgenics for age-matched comparisons. Mice were housed in a specific pathogen free conventional animal facility and standard breeding practices were used to generate F1 hybrids resulting in the expected Mendelian proportions of: 25% non-transgenic (wildtype), 25% APOL1 single transgenic, 25% Tg26/HIVAN4 single transgenic, and 25% APOL1 plus Tg26/HIVAN4 dual transgenic mice.…”

Genetic Association and Gene-Gene Interaction Analyses in African American Dialysis Patients With Nondiabetic Nephropathy

“…The interaction between NPHS2 and APOL1 , both clearly replicated and powerful effect nephropathy genes, is likely to be clinically relevant and potentially useful for screening in high risk populations. Interactions exist between Nphs2 and HIVAN1 / HIVAN2 in the HIV-1 transgenic mouse model of collapsing FSGS 33, 34 .…”

APOL1 is not expressed in proximal tubules and is not filtered

“…BAC-APOL1 transgenic lines were backcrossed to FVB/Nj for this study. The mouse model of HIVAN used to induce proteinuria was the Tg26 HIVAN4 congenic that develops a less aggressive disease than the parental Tg26 model and has been previously described (18). Intercrossed BAC-APOL1 transgenic mice with HIVAN4 mice were sacrificed at ~45 days of age when proteinuria was >2+ by urine dipstick (G0 n=15, G1 n=11, G2 n=9).…”