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

• Published in: Kidney international Vol. 75; no. 4; pp. 366 - 372
• Main Authors: Chan, Ka T., Papeta, Natalia, Martino, Jeremiah, Zheng, Zongyu, Frankel, Rachelle Z., Klotman, Paul E., D'Agati, Vivette D., Lifton, Richard P., Gharavi, Ali G.
• Format: Journal Article
• Language: English
• Published: Basingstoke Elsevier Inc 01-02-2009; Nature Publishing Group; Elsevier Limited
• Subjects: AIDS-Associated Nephropathy - genetics; Animals; Biological and medical sciences; Chromosome Mapping; Chromosomes; Disease Progression; Genetic Predisposition to Disease; genetic susceptibility; Glomerulonephritis; Glomerulonephritis - genetics; Glomerulonephritis - pathology; HIV-1 - genetics; HIV-associated nephropathy; Human viral diseases; Infectious diseases; Medical sciences; Mice; Mice, Congenic; mouse model; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; HIV-associated nephropathy; mouse model; genetic susceptibility; Glomerulonephritis; Animal model; Nephrology; Genetic determinism; Urology; Development; Congenic; Locus; Kidney disease; Immunopathology; Urinary system disease; Rodentia; Retroviridae; AIDS; Immune deficiency; Lentivirus; Infection; Virus; Vertebrata; Mammalia; Mouse; Viral disease; Animal; Human immunodeficiency virus; Collapsing glomerulonephritis
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1038/ki.2008.625

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-HIVAN1CAST 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.