Accelerated development of collapsing glomerulopathy in mice congenic for the HIVAN1 locus.
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.
Chan
Ka T
KT
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA.
Papeta
Natalia
N
Martino
Jeremiah
J
Zheng
Zongyu
Z
Frankel
Rachelle Z
RZ
Klotman
Paul E
PE
D'Agati
Vivette D
VD
Lifton
Richard P
RP
Gharavi
Ali G
AG
D016263:AIDS-Associated Nephropathy / Q000235:genetics*; D000818:Animals; D002874:Chromosome Mapping; D002875:Chromosomes; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D005921:Glomerulonephritis / Q000235:genetics* / Q000473:pathology; D015497:HIV-1 / Q000235:genetics*; D051379:Mice; D020297:Mice, Congenic