Oxidative stress pathways in the pathogenesis of renal fibrosis

Eltoweissy, Marwa

Multiple cellular stress proteins as regulative molecules and therapeutic targets

dc.contributor.advisor	Wimmer, Ernst A. Prof. Dr.
dc.contributor.author	Eltoweissy, Marwa
dc.date.accessioned	2016-05-23T09:23:37Z
dc.date.available	2016-05-23T09:23:37Z
dc.date.issued	2016-05-23
dc.identifier.uri	http://hdl.handle.net/11858/00-1735-0000-0028-875B-8
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-5627
dc.language.iso	eng	de
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc	570	de
dc.title	Oxidative stress pathways in the pathogenesis of renal fibrosis	de
dc.title.alternative	Multiple cellular stress proteins as regulative molecules and therapeutic targets
dc.type	doctoralThesis	de
dc.contributor.referee	Wimmer, Ernst A. Prof. Dr.
dc.date.examination	2015-02-12
dc.description.abstracteng	In 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 DJ-1.	de
dc.contributor.coReferee	Groß, Uwe Prof. Dr.
dc.subject.eng	Protein DJ-1	de
dc.subject.eng	Kidney	de
dc.subject.eng	Renal cells	de
dc.subject.eng	Hydrogen peroxide	de
dc.subject.eng	Angiotensin	de
dc.subject.eng	PDGF	de
dc.subject.eng	Oxidative stress	de
dc.subject.eng	Renal fibrosis	de
dc.subject.eng	DJ-1 mutants	de
dc.subject.eng	DJ-1 wild type	de
dc.subject.eng	Immunoprecipitation	de
dc.subject.eng	Cell viability	de
dc.subject.eng	Immunostaining	de
dc.identifier.urn	urn:nbn:de:gbv:7-11858/00-1735-0000-0028-875B-8-4
dc.affiliation.institute	Biologische Fakultät für Biologie und Psychologie	de
dc.subject.gokfull	Biologie (PPN619462639)	de
dc.identifier.ppn	859718689

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