Identification of the Nephropathy-Susceptibility Locus HIVAN4

Prakash, Sindhuri; Papeta, Natalia; Sterken, Roel; Zheng, Zongyu; Thomas, Robert; Wu, Zhenzhen; Sedor, John R.; D’Agati, Vivette D.; Bruggeman, Leslie A.; Gharavi, Ali G.

doi:10.1681/asn.2011020209

Cited by 11 publications

(16 citation statements)

References 39 publications

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“…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.…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

Section: Mouse Models and Phenotypingmentioning

confidence: 99%

“…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.…”

Section: Mouse Models and Phenotypingmentioning

confidence: 99%

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

Bruggeman

Luo

et al. 2019

Preprint

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Background: African polymorphisms in the gene for Apolipoprotein L1 (APOL1) confer a survival advantage against lethal trypanosomiasis but also an increased risk for several chronic kidney diseases (CKD) including HIV-associated nephropathy (HIVAN). APOL1 is expressed in renal cells, however, the pathogenic events that lead to renal cell damage and kidney disease are not fully understood. Methods:The podocyte function of APOL1-G0 versus APOL1-G2 in the setting of a known disease stressor was assessed using transgenic mouse models. Survival, renal pathology and function, and podocyte density were assessed in an intercross of a mouse model of HIVAN (Tg26) with two mouse models that express either APOL1-G0 or APOL1-G2 in podocytes. Results:Mice that expressed HIV genes developed heavy proteinuria and glomerulosclerosis, and had significant losses in podocyte numbers and reductions in podocyte densities. Mice that coexpressed APOL1-G0 and HIV had preserved podocyte numbers and densities, with fewer morphologic manifestations typical of HIVAN pathology. Podocyte losses and pathology in mice co-expressing APOL1-G2 and HIV were not significantly different from mice expressing only HIV. Podocyte hypertrophy, a known compensatory event to stress, was increased in the mice coexpressing HIV and APOL1-G0, but absent in the mice co-expressing HIV and APOL1-G2. Mortality and renal function tests were not significantly different between groups.Conclusions: APOL1-G0 expressed in podocytes may have a protective function against podocyte loss or injury when exposed to an environmental stressor. This function appears to be absent with APOL1-G2 expression, suggesting APOL1-G2 is a loss-of-function variant.

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Section: Resultsmentioning

confidence: 99%

Section: Mouse Models and Phenotypingmentioning

confidence: 99%

Section: Mouse Models and Phenotypingmentioning

confidence: 99%

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

Bruggeman

Luo

et al. 2019

Preprint

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“…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 .…”

Section: Discussionmentioning

confidence: 99%

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

Bostrom

Kao

et al. 2012

American Journal of Kidney Diseases

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Background African Americans (AAs) have increased susceptibility to non-diabetic nephropathy relative to European Americans. Study Design Follow-up of a pooled genome-wide association study (GWAS) in AA dialysis patients with nondiabetic nephropathy; novel gene-gene interaction analyses. Setting & Participants Wake Forest sample: 962 AA nondiabetic nephropathy cases; 931 non-nephropathy controls. Replication sample: 668 Family Investigation of Nephropathy and Diabetes (FIND) AA nondiabetic nephropathy cases; 804 non-nephropathy controls. Predictors Individual genotyping of top 1420 pooled GWAS-associated single nucleotide polymorphisms (SNPs) and 54 SNPs in six nephropathy susceptibility genes. Outcomes APOL1 genetic association and additional candidate susceptibility loci interacting with, or independently from, APOL1. Results The strongest GWAS associations included two non-coding APOL1 SNPs, rs2239785 (odds ratio [OR], 0.33; dominant; p = 5.9 × 10−24) and rs136148 (OR, 0.54; additive; p = 1.1 × 10−7) with replication in FIND (p = 5.0 × 10−21 and 1.9 × 10−05, respectively). Rs2239785 remained significantly associated after controlling for the APOL1 G1 and G2 coding variants. Additional top hits included a CFH SNP(OR from meta-analysis in above 3367 AA cases and controls, 0.81; additive; p = 6.8 × 10−4). The 1420 SNPs were tested for interaction with APOL1 G1 and G2 variants. Several interactive SNPs were detected, the most significant was rs16854341 in the podocin gene (NPHS2) (p = 0.0001). Limitations Non-pooled GWAS have not been performed in AA nondiabetic nephropathy. Conclusions This follow-up of a pooled GWAS provides additional and independent evidence that APOL1 variants contribute to nondiabetic nephropathy in AAs and identified additional associated and interactive non-diabetic nephropathy susceptibility genes.

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“…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).…”

Section: Short Methodsmentioning

confidence: 99%

APOL1 is not expressed in proximal tubules and is not filtered

Blessing

Madhavan

et al. 2019

Preprint

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The kidney expression pattern of APOL1 was examined using both protein and mRNA in situ methods on APOL1 bacterial artificial chromosome transgenic mice, with and without proteinuria.APOL1 was detected in podocytes and endothelial cells of the kidney, but was not expressed in tubular epithelia, nor was plasma APOL1 protein filtered and reabsorbed by the proximal tubule. APOL1 expression in podocytes and endothelia should remain the focus for mechanistic studies of APOL1-mediated pathogenesis.

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Identification of the Nephropathy-Susceptibility Locus HIVAN4

Cited by 11 publications

References 39 publications

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

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

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

APOL1 is not expressed in proximal tubules and is not filtered

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