Inhibition of endoplasmic reticulum stress signaling rescues cytotoxicity of human apolipoprotein-L1 risk variants in Drosophila
Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved..
Risk variants of the apolipoprotein-L1 (APOL1) gene are associated with severe kidney disease, putting homozygous carriers at risk. Since APOL1 lacks orthologs in all major model organisms, a wide range of mechanisms frequently in conflict have been described for APOL1-associated nephropathies. The genetic toolkit in Drosophila allows unique in vivo insights into disrupted cellular homeostasis. To perform a mechanistic analysis, we expressed human APOL1 control and gain-of-function kidney risk variants in the podocyte-like garland cells of Drosophila nephrocytes and a wing precursor tissue. Expression of APOL1 risk variants was found to elevate endocytic function of garland cell nephrocytes that simultaneously showed early signs of cell death. Wild-type APOL1 had a significantly milder effect, while a control transgene with deletion of the short BH3 domain showed no overt phenotype. Nephrocyte endo-lysosomal function and slit diaphragm architecture remained unaffected by APOL1 risk variants, but endoplasmic reticulum (ER) swelling, chaperone induction, and expression of the reporter Xbp1-EGFP suggested an ER stress response. Pharmacological inhibition of ER stress diminished APOL1-mediated cell death and direct ER stress induction enhanced nephrocyte endocytic function similar to expression of APOL1 risk variants. We confirmed APOL1-dependent ER stress in the Drosophila wing precursor where silencing the IRE1-dependent branch of ER stress signaling by inhibition with Xbp1-RNAi abrogated cell death, representing the first rescue of APOL1-associated cytotoxicity in vivo. Thus, we uncovered ER stress as an essential consequence of APOL1 risk variant expression in vivo in Drosophila, suggesting a central role of this pathway in the pathogenesis of APOL1-associated nephropathies.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:101 |
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| Enthalten in: |
Kidney international - 101(2022), 6 vom: 15. Juni, Seite 1216-1231 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gerstner, Lea [VerfasserIn] |
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| Links: |
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| Themen: |
APOL1 |
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| Anmerkungen: |
Date Completed 24.05.2022 Date Revised 31.03.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.kint.2021.12.031 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM336535384 |
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| 520 | |a Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Risk variants of the apolipoprotein-L1 (APOL1) gene are associated with severe kidney disease, putting homozygous carriers at risk. Since APOL1 lacks orthologs in all major model organisms, a wide range of mechanisms frequently in conflict have been described for APOL1-associated nephropathies. The genetic toolkit in Drosophila allows unique in vivo insights into disrupted cellular homeostasis. To perform a mechanistic analysis, we expressed human APOL1 control and gain-of-function kidney risk variants in the podocyte-like garland cells of Drosophila nephrocytes and a wing precursor tissue. Expression of APOL1 risk variants was found to elevate endocytic function of garland cell nephrocytes that simultaneously showed early signs of cell death. Wild-type APOL1 had a significantly milder effect, while a control transgene with deletion of the short BH3 domain showed no overt phenotype. Nephrocyte endo-lysosomal function and slit diaphragm architecture remained unaffected by APOL1 risk variants, but endoplasmic reticulum (ER) swelling, chaperone induction, and expression of the reporter Xbp1-EGFP suggested an ER stress response. Pharmacological inhibition of ER stress diminished APOL1-mediated cell death and direct ER stress induction enhanced nephrocyte endocytic function similar to expression of APOL1 risk variants. We confirmed APOL1-dependent ER stress in the Drosophila wing precursor where silencing the IRE1-dependent branch of ER stress signaling by inhibition with Xbp1-RNAi abrogated cell death, representing the first rescue of APOL1-associated cytotoxicity in vivo. Thus, we uncovered ER stress as an essential consequence of APOL1 risk variant expression in vivo in Drosophila, suggesting a central role of this pathway in the pathogenesis of APOL1-associated nephropathies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a APOL1 | |
| 650 | 4 | |a Drosophila | |
| 650 | 4 | |a endoplasmic reticulum stress | |
| 650 | 4 | |a focal segmental glomerular sclerosis | |
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| 650 | 7 | |a Apolipoprotein L1 |2 NLM | |
| 700 | 1 | |a Chen, Mengmeng |e verfasserin |4 aut | |
| 700 | 1 | |a Kampf, Lina L |e verfasserin |4 aut | |
| 700 | 1 | |a Milosavljevic, Julian |e verfasserin |4 aut | |
| 700 | 1 | |a Lang, Konrad |e verfasserin |4 aut | |
| 700 | 1 | |a Schneider, Ronen |e verfasserin |4 aut | |
| 700 | 1 | |a Hildebrandt, Friedhelm |e verfasserin |4 aut | |
| 700 | 1 | |a Helmstädter, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Walz, Gerd |e verfasserin |4 aut | |
| 700 | 1 | |a Hermle, Tobias |e verfasserin |4 aut | |
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