Accelerated development of collapsing glomerulopathy in mice congenic for the HIVAN1 locus

Abstract

HIV-1 transgenic mice on the FVB/NJ background (TgFVB) are a well validated model of HIV-associated nephropathy (HIVAN). A mapping study between TgFVB and CAST/EiJ (CAST) strains showed this trait to be influenced by a major susceptibility locus on chromosome 3A1-A3 (HIVAN1), with CAST alleles associated with increased risk of disease. We introgressed a 50 Mb interval, encompassing this HIVAN1 locus, from CAST into the TgFVB genome (TgFVB-HIVAN1(CAST) congenic mice). Compared to the TgFVB strain, these congenic mice developed an earlier onset of proteinuria, a rapid progression to kidney failure, and increased mortality. A prospective study of these congenic mice also showed that they had a significantly greater histologic and biochemical evidence of glomerulopathy with one-third of mice developing global glomerulosclerosis by 6 weeks of age. An F2 cross between TgFVB and the congenic mice identified a significant linkage (LOD=3.7) to a 10 cM interval within the HIVAN1 region between D3Mit167 and D3Mit67 resulting in a 60% reduction of the original interval. These data independently confirm that a gene on chromosome 3A1-A3 increases susceptibility to HIVAN, resulting in early onset and rapid progression of kidney disease. These mice represent a new model to study the development and progression of collapsing glomerulopathy.

Figure 1

Histology of in FVB-HIVAN1^CAST mice (PAS stain). Congenic mice display advanced global glomerulosclerosis (A–C) or collapsing glomerulosclerosis with podocyte hyperplasia (D–F). A & D. Low power view (x200) demonstrates diffuse and global glomerulosclerosis, extensive microcystic tubular dilatation and severe tubulo-interstitial injury. B, C High power views (x 400) of glomeruli showing global sclerosis and podocyte depletion. Higher power views (x 600) of glomeruli showing collapsing sclerosis (E) with podocyte hyperplasia and cytoplasmic vacuolization (F).

Figure 2

Comparison of proteinuria (A) and glomerulosclerosis scores (B) in HIV-1 transgenic mice carrying different alleles at the HIVAN1 locus on chr 3A1-A3. Values for a cohort of nontransgenic (nonTg) mice of all three genotypes are shown for comparisons. # P<0.005, * p<0.05 vs Tg FVB/FVB genotype

Figure 3

A. Lod plots for renal histology scores in the F2 intercross between TgFVB and FVB-HIVAN1^CAST strains. Map distance is presented in cM. The positions of informative markers are shown above each plot. The dashed horizontal lines indicate the empiric threshold for 95^th and 99^th percentile significance level based on 10,000 permutations (1.9 and 3.2, respectively). The 95^th confidence interval for the location of the HIVAN1 gene is shown above the lod plot. B. Phenotypic effects of HIVAN1 genotype in F2 cross is consistent with an additive model (mean +/− SEM)