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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.

SUBMITTER: Chan KT

PROVIDER: S-EPMC2753461 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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

Chan Ka T KT 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

Kidney international 20081217 4

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 ...[more]

PMID: 19092797

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Project description:Background and objectivesMalaria, a potentially life-threatening disease, is the most prevalent endemic infectious disease worldwide. In the modern era, the spectrum of glomerular involvement observed in patients after malarial infections remains poorly described.Design, setting, participants, & measurementsWe therefore performed a retrospective multicenter study to assess the clinical, biologic, pathologic, and therapeutic characteristics of patients with glomerular disease demonstrated by kidney biopsy in France within 3 months of an acute malaria episode.ResultsWe identified 23 patients (12 men), all but 1 of African ancestry and including 10 patients with concomitant HIV infection. All of the imported cases were in French citizens living in France who had recently traveled back to France from an endemic area and developed malaria after their return to France. Eleven patients had to be admitted to an intensive care unit at presentation. Plasmodium falciparum was detected in 22 patients, and Plasmodium malariae was detected in 1 patient. Kidney biopsy was performed after the successful treatment of malaria, a mean of 24 days after initial presentation. At this time, all patients displayed AKI, requiring KRT in 12 patients. Nephrotic syndrome was diagnosed in 17 patients. Pathologic findings included FSGS in 21 patients and minimal change nephrotic syndrome in 2 patients. Among patients with FSGS, 18 had collapsing glomerulopathy (including 9 patients with HIV-associated nephropathy). In four patients, immunohistochemistry with an antibody targeting P. falciparum histidine-rich protein-2 demonstrated the presence of the malaria antigen in tubular cells but not in podocytes or parietal epithelial cells. An analysis of the apoL1 risk genotype showed that high-risk variants were present in all seven patients tested. After a mean follow-up of 23 months, eight patients required KRT (kidney transplantation in two patients), and mean eGFR for the other patients was 51 ml/min per 1.73 m2.ConclusionsIn patients of African ancestry, imported Plasmodium infection may be a new causal factor for secondary FSGS, particularly for collapsing glomerulopathy variants in an APOL1 high-risk variant background.

Dataset Information

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

Publications

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

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