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Oxidative stress pathways in the pathogenesis of renal fibrosis

Multiple cellular stress proteins as regulative molecules and therapeutic targets

dc.contributor.advisorWimmer, Ernst A. Prof. Dr.
dc.contributor.authorEltoweissy, Marwa
dc.titleOxidative stress pathways in the pathogenesis of renal fibrosisde
dc.title.alternativeMultiple cellular stress proteins as regulative molecules and therapeutic targets
dc.contributor.refereeWimmer, Ernst A. Prof. Dr.
dc.description.abstractengIn the pathogenesis of renal fibrosis, oxidative stress (OS) enhances the production of reactive oxygen species (ROS) leading to sustained cell growth, inflammation, excessive tissue remodelling and accumulation, which results in the development and acceleration of renal damage. In our previous work (128) we established protein DJ-1 (PARK7) as an important ROS scavenger and key player in renal cell response to OS. In the present study we investigated the impact of profibrogenic agonists on DJ-1 and shed light on the role of this protein in renal fibrosis. Treatment of renal fibroblasts and epithelial cells with the profibrogenic agonist ANG II or PDGF resulted in a significant up-regulation of DJ-1 expression parallel to an increase in the expression of fibrosis markers. Monitoring of DJ-1 expression in kidney extract and tissue sections from renal fibrosis mice model (Col4a3-deficient) revealed a disease grad dependent regulation of the protein. Overexpression of DJ-1 prompted cell resistance to OS in both fibroblasts and epithelial cells. Furthermore overexpression of DJ-1 mutant for glutamic acid 18 (E18), involved in ROS scavenging, in which glutamic acid 18 (E18) is mutated to either aspartic acid (D) or glutamine (Q) resulted in a significant increase in cell death under OS in case of E18D mutation. Whereas the E18Q mutation did not impact significantly the cell response to OS, revealing the importance of the acidic group for protein DJ-1 as ROS scavenging more than the nature of amino acid itself. Affinity precipitation of interaction partners of DJ-1 and its mutants revealed both: a consistent proteomic cascade that has substantial physiological and pathological properties in collaboration with protein DJ-1 and, an important role of Annexin A1 and A5 in the mechanism of action of DJ-1 in anti-oxidative stress response. In addition, provided evidence for DJ-1 diverse functions; as an oxidative sensor, a chaperone and/or its role at the transcriptional and posttranscriptional levels. Consequently, our results support the view that cellular adaptation to OS is accompanied by modulation of coordinated cellular and molecular events, suggest a direct correlation of fibrosis progression and expression of OS proteins, emphasize the current evidence for how the oxidative modification may regulate DJ-1’s protective function, and implicate a multistep pathway for the paramount protein
dc.contributor.coRefereeGroß, Uwe Prof. Dr.
dc.subject.engProtein DJ-1de
dc.subject.engRenal cellsde
dc.subject.engHydrogen peroxidede
dc.subject.engOxidative stressde
dc.subject.engRenal fibrosisde
dc.subject.engDJ-1 mutantsde
dc.subject.engDJ-1 wild typede
dc.subject.engCell viabilityde
dc.affiliation.instituteBiologische Fakultät für Biologie und Psychologiede
dc.subject.gokfullBiologie (PPN619462639)de

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