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Chen, Mengmeng [VerfasserIn] ; Walz, Gerd [AkademischeR BetreuerIn]; Hermle, Tobias Franz [AkademischeR BetreuerIn]; Walz, Gerd [Sonstige Person, Familie und Körperschaft]; Sekula, Peggy [Sonstige Person, Familie und Körperschaft] Albert-Ludwigs-Universität Freiburg Medizinische Fakultät

Using transgenic Drosophila model to study the mechanism of APOL1-associated cytotoxicity

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  • Medientyp: E-Book
  • Titel: Using transgenic Drosophila model to study the mechanism of APOL1-associated cytotoxicity
  • Beteiligte: Chen, Mengmeng [Verfasser]; Walz, Gerd [Akademischer Betreuer]; Hermle, Tobias Franz [Akademischer Betreuer]; Walz, Gerd [Sonstige]; Sekula, Peggy [Sonstige]
  • Körperschaft: Albert-Ludwigs-Universität Freiburg, Medizinische Fakultät
  • Erschienen: Freiburg: Universität, 2022
  • Umfang: Online-Ressource
  • Sprache: Englisch
  • DOI: 10.6094/UNIFR/230802
  • Identifikator:
  • Schlagwörter: Taufliege ; Signaltransduktion ; Fokal-segmentale Glomerulosklerose ; (local)doctoralThesis
  • Entstehung:
  • Hochschulschrift: Dissertation, Universität Freiburg, 2022
  • Anmerkungen:
  • Beschreibung: Abstract: The high prevalence of G1-APOL1 and G2-APOL1 risk variants among African populations is due to the fact that the two risk alleles protect humans from infection by Trypanosoma brucei rhodesiense. However, subjects of African ancestry carrying APOL1 risk alleles are at an increased risk of developing focal segmental glomerulosclerosis (FSGS) and end-stage renal disease (ESRD). Given that most primates lack APOL1 orthologs and the lack of phenotypes in individuals carrying APOL1 null alleles, we hypothesized that G1-APOL1 and G2-APOL1 are gain-of-function variants. We generated transgenic Drosophila bearing either the wild-type (G0), G1 or G2 forms of human APOL1. Our findings established that the major intracellular localization of APOL1 protein in fly was the endoplasmic reticulum (ER). APOL1 risk variants induced severe ER stress in Drosophila wing disc cells by specifically activating the IRE1- Xbp1-dependent branch of ER stress signaling. With persistent induction of ER stress in wing disc cells, excessive apoptosis was triggered. Importantly, both a genetic approach silencing Xbp1 gene expression and a pharmacological method applying ER stress inhibitor 4-Phenyl butyric acid (4-PBA) successfully rescued APOL1-related apoptosis in Drosophila larvae. Our data from mammalian cells demonstrated similar results. Administration of interferon gamma resulted in upregulation of endogenous APOL1 protein levels in cultured human podocytes. Overexpression of either of the APOL1 risk variants in HEK293T cells caused significant ER stress. The using of 4-PBA effectively relieved ER stress, suggesting that ER stress is the essential step of cytotoxicity related to APOL1 risk variants.<br>Taken together, these findings shed light on the pathogenesis of APOL1-assocaited nephropathy and present an important animal model for future therapeutic studies
  • Zugangsstatus: Freier Zugang