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APOL1-Mediated Cell Injury Involves Disruption of Conserved Trafficking Processes.

ABSTRACT: APOL1 harbors C-terminal sequence variants (G1 and G2), which account for much of the increased risk for kidney disease in sub-Saharan African ancestry populations. Expression of the risk variants has also been shown to cause injury to podocytes and other cell types, but the underlying mechanisms are not understood. We used Drosophila melanogaster and Saccharomyces cerevisiae to help clarify these mechanisms. Ubiquitous expression of the human APOL1 G1 and G2 disease risk alleles caused near-complete lethality in D. melanogaster, with no effect of the G0 nonrisk APOL1 allele, corresponding to the pattern of human disease risk. We also observed a congruent pattern of cellular damage with tissue-specific expression of APOL1. In particular, expression of APOL1 risk variants in D. melanogaster nephrocytes caused cell-autonomous accumulation of the endocytic tracer atrial natriuretic factor-red fluorescent protein at early stages and nephrocyte loss at later stages. We also observed differential toxicity of the APOL1 risk variants compared with the APOL1 nonrisk variants in S. cerevisiae, including impairment of vacuole acidification. Yeast strains defective in endosomal trafficking or organelle acidification but not those defective in autophagy displayed augmented APOL1 toxicity with all isoforms. This pattern of differential injury by the APOL1 risk alleles compared with the nonrisk alleles across evolutionarily divergent species is consistent with an impairment of conserved core intracellular endosomal trafficking processes. This finding should facilitate the identification of cell injury pathways and corresponding therapeutic targets of interest in these amenable experimental platforms.

SUBMITTER: Kruzel-Davila E

PROVIDER: S-EPMC5373454 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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APOL1-Mediated Cell Injury Involves Disruption of Conserved Trafficking Processes.

Kruzel-Davila Etty E Shemer Revital R Ofir Ayala A Bavli-Kertselli Ira I Darlyuk-Saadon Ilona I Oren-Giladi Pazit P Wasser Walter G WG Magen Daniella D Zaknoun Eid E Schuldiner Maya M Salzberg Adi A Kornitzer Daniel D Marelja Zvonimir Z Simons Matias M Skorecki Karl K

Journal of the American Society of Nephrology : JASN 20161118 4

APOL1 harbors C-terminal sequence variants (G1 and G2), which account for much of the increased risk for kidney disease in sub-Saharan African ancestry populations. Expression of the risk variants has also been shown to cause injury to podocytes and other cell types, but the underlying mechanisms are not understood. We used Drosophila melanogaster and Saccharomyces cerevisiae to help clarify these mechanisms. Ubiquitous expression of the human APOL1 G1 and G2 disease risk al ...[more]

PMID: 27864431

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Project description:Purpose: Vascular damage and inflammation are limiting toxic effects of lung cancer radiotherapy, which lead to pneumonitis and pulmonary fibrosis. We have demonstrated that soy isoflavones (SIF) mitigate these toxic effects at late time points after radiation. However, the process by which SIF impacts the onset of radiation-induced inflammation remains to be elucidated. We have now investigated early events of radiation-induced inflammation and identified cellular and molecular signaling patterns by endothelial cells that could be modified by SIF to control vascular damage and the initiation of lung inflammation.Materials and methods: Histopathological, cellular and molecular studies were performed on mouse lungs from C57Bl/6 mice treated with 10?Gy of thoracic radiation (XRT) in conjunction with daily oral SIF treatment given prior and after radiation. Parallel studies were performed in-vitro using EA.hy926 endothelial cell line with SIF and radiation. Immunohistochemistry, western blots analysis, and flow cytometry were performed on lung tissue or EA.hy926 cells to analyze endothelial cells, their patterns of cell death or survival, and signaling molecules involved in inflammatory events.Results: Histopathological differences in inflammatory infiltrates and vascular injury in lungs, including vascular endothelial cells, were observed with SIF treatment at early time points post-XRT. XRT-induced expression of proinflammatory adhesion molecule ICAM-1 cells was reduced by SIF in-vitro and in-vivo in endothelial cells. Molecular changes in endothelial cells with SIF treatment in conjunction with XRT included increased DNA damage, reduced cell viability and cyclin B1, and inhibition of nuclear translocation of NF-?B. Analysis of cell death showed that SIF treatment promoted apoptotic endothelial cell death and decreased XRT-induced type III cell death. In-vitro molecular studies indicated that SIF?+?XRT increased apoptotic caspase-9 activation and production of IFN? while reducing the release of inflammatory HMGB-1 and IL-1?, the cleavage of pyroptotic gasdermin D, and the release of active IL-1?, which are all events associated with type III cell death.Conclusions: SIF?+?XRT caused changes in patterns of endothelial cell death and survival, proinflammatory molecule release, and adhesion molecule expression at early time points post-XRT associated with early reduction of immune cell recruitment. These findings suggest that SIF could mediate its radioprotective effects in irradiated lungs by limiting excessive immune cell homing via vascular endothelium into damaged lung tissue and curtailing the overall inflammatory response to radiation.

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APOL1-Mediated Cell Injury Involves Disruption of Conserved Trafficking Processes.

Publications

APOL1-Mediated Cell Injury Involves Disruption of Conserved Trafficking Processes.

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