Lessons From APOL1 Animal Models

Yoshida, Teruhiko; Latt, Khun Zaw; Heymann, Jürgen; Kopp, Jeffrey B.

doi:10.3389/fmed.2021.762901

Cited by 8 publications

(6 citation statements)

References 37 publications

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“…To overcome these experimental limitations, several transgenic APOL1 mouse models have been developed using different experimental approaches [ 19 – 25 ]. In general, these models support the notion that the kidney disease is a function of the expression level of the APOL1 in podocytes, and describe different mechanisms through which the risk variants may induce CKD (recently reviewed in detail [ 26 ]). One limitation of these transgenic mouse models is that they cannot be used in genetic screens to identify interacting proteins that modify the toxicity of APOL1.…”

Section: Introductionsupporting

confidence: 57%

A SNARE protective pool antagonizes APOL1 renal toxicity in Drosophila nephrocytes

Lee,

Fu,

Zhu

et al. 2023

Cell Biosci

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Background People of Sub-Saharan African ancestry are at higher risk of developing chronic kidney disease (CKD), attributed to the Apolipoprotein L1 (APOL1) gene risk alleles (RA) G1 and G2. The underlying mechanisms by which the APOL1-RA precipitate CKD remain elusive, hindering the development of potential treatments. Results Using a Drosophila genetic modifier screen, we found that SNARE proteins (Syx7, Ykt6, and Syb) play an important role in preventing APOL1 cytotoxicity. Reducing the expression of these SNARE proteins significantly increased APOL1 cytotoxicity in fly nephrocytes, the equivalent of mammalian podocytes, whereas overexpression of Syx7, Ykt6, or Syb attenuated their toxicity in nephrocytes. These SNARE proteins bound to APOL1-G0 with higher affinity than APOL1-G1/G2, and attenuated APOL1-G0 cytotoxicity to a greater extent than either APOL1-RA. Conclusions Using a Drosophila screen, we identified SNARE proteins (Syx7, Ykt6, and Syb) as antagonists of APOL1-induced cytotoxicity by directly binding APOL1. These data uncovered a new potential protective role for certain SNARE proteins in the pathogenesis of APOL1-CKD and provide novel therapeutic targets for APOL1-associated nephropathies.

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Section: Introductionsupporting

confidence: 57%

A SNARE protective pool antagonizes APOL1 renal toxicity in Drosophila nephrocytes

Lee,

Fu,

Zhu

et al. 2023

Cell Biosci

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“…While many mechanisms have been reported in cell culture models, few have been demonstrated to be active in transgenic mouse models. 3,8 APOL1 is believed to cause podocyte damage primarily via endogenous expression, as reported in podocyte-specific over-expression mouse models. 9,10 There have been several reports investigating mechanism of APOL1 disease using a bacterial artificial chromosome (BAC)/APOL1 transgenic mouse model, which mimics human APOL1 expression under the regulation of the human APOL1 promotor and other regulatory genetic elements.…”

Section: Introductionmentioning

confidence: 92%

APOL1 kidney risk variants in glomerular diseases modeled in transgenic mice

Yoshida

Latt

Santo

et al. 2023

Preprint

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APOL1 high-risk variants partially explain the high kidney disease prevalence among African ancestry individuals. Many mechanisms have been reported in cell culture models, but few have been demonstrated in mouse models. Here we characterize two models: (1) HIV-associated nephropathy (HIVAN) Tg26 mice crossed with bacterial artificial chromosome (BAC)/APOL1 transgenic mice and (2) interferon-g; administered to BAC/APOL1 mice. Both models showed exacerbated glomerular disease in APOL1-G1 compared to APOL1-G0 mice. HIVAN model glomerular bulk RNA-seq identified synergistic podocyte-damaging pathways activated by the APOL1-G1 allele and by HIV transgenes. Single-nuclear RNA-seq revealed podocyte-specific patterns of differentially-expressed genes as a function of APOL1 alleles. Eukaryotic Initiation factor-2 pathway was the most activated pathway in the interferon-g; model and the most deactivated pathway in the HIVAN model. HIVAN mouse model podocyte single-nuclear RNA-seq data showed similarity to human focal segmental glomerulosclerosis (FSGS) glomerular bulk RNA-seq data. Furthermore, single-nuclear RNA-seq data from interferon-g; mouse model podocytes (in vivo) showed similarity to human FSGS single-cell RNA-seq data from urine podocytes (ex vivo) and from human podocyte cell lines (in vitro) using bulk RNA-seq. These data highlight differences in the transcriptional effects of the APOL1-G1 risk variant in a model specific manner. Shared differentially expressed genes in podocytes in both mouse models suggest possible novel glomerular damage markers in APOL1 variant-induced diseases. Transcription factor Zbtb16 was downregulated in podocytes and endothelial cells in both models, possibly contributing to glucocorticoid-resistance. In summary, these findings in two mouse models suggest both shared and distinct therapeutic opportunities for APOL1 glomerulopathies.

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“…Up to now, almost all mouse experiments have used models that express APOL1 in the podocyte [ 50 , 58 – 60 ]. The results from the novel mouse model described here provide some support for the hypothesis that plasma APOL1, particularly APOL1-G1, could synergize with APOL1 protein expressed in podocytes to exacerbate renal injury.…”

Section: Discussionmentioning

confidence: 99%

Variant APOL1 protein in plasma associates with larger particles in humans and mouse models of kidney injury

Andrews

Yoshida²,

Henderson³

et al. 2022

PLoS ONE

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Background Genetic variants in apolipoprotein L1 (APOL1), a protein that protects humans from infection with African trypanosomes, explain a substantial proportion of the excess risk of chronic kidney disease affecting individuals with sub-Saharan ancestry. The mechanisms by which risk variants damage kidney cells remain incompletely understood. In preclinical models, APOL1 expressed in podocytes can lead to significant kidney injury. In humans, studies in kidney transplant suggest that the effects of APOL1 variants are predominantly driven by donor genotype. Less attention has been paid to a possible role for circulating APOL1 in kidney injury. Methods Using liquid chromatography-tandem mass spectrometry, the concentrations of APOL1 were measured in plasma and urine from participants in the Seattle Kidney Study. Asymmetric flow field-flow fractionation was used to evaluate the size of APOL1-containing lipoprotein particles in plasma. Transgenic mice that express wild-type or risk variant APOL1 from an albumin promoter were treated to cause kidney injury and evaluated for renal disease and pathology. Results In human participants, urine concentrations of APOL1 were correlated with plasma concentrations and reduced kidney function. Risk variant APOL1 was enriched in larger particles. In mice, circulating risk variant APOL1-G1 promoted kidney damage and reduced podocyte density without renal expression of APOL1. Conclusions These results suggest that plasma APOL1 is dynamic and contributes to the progression of kidney disease in humans, which may have implications for treatment of APOL1-associated kidney disease and for kidney transplantation.

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Lessons From APOL1 Animal Models

Cited by 8 publications

References 37 publications

A SNARE protective pool antagonizes APOL1 renal toxicity in Drosophila nephrocytes

A SNARE protective pool antagonizes APOL1 renal toxicity in Drosophila nephrocytes

APOL1 kidney risk variants in glomerular diseases modeled in transgenic mice

Variant APOL1 protein in plasma associates with larger particles in humans and mouse models of kidney injury

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