Untersuchung der pharmakologischen Modulation von ARNT-Homodimeren auf die Renoprotektion

Rapp, Gregor Christof

dc.contributor.advisor	Zeisberg, Michael Prof. Dr.
dc.contributor.author	Rapp, Gregor Christof
dc.date.accessioned	2023-10-02T16:40:01Z
dc.date.available	2023-10-19T00:50:12Z
dc.date.issued	2023-10-02
dc.identifier.uri	http://resolver.sub.uni-goettingen.de/purl?ediss-11858/14898
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-10120
dc.format.extent	102	de
dc.language.iso	deu	de
dc.subject.ddc	610	de
dc.title	Untersuchung der pharmakologischen Modulation von ARNT-Homodimeren auf die Renoprotektion	de
dc.type	doctoralThesis	de
dc.title.translated	The pharmacological effect of ARNT homodimers on renoprotection	de
dc.contributor.referee	Neeße, Albrecht Prof Dr. Dr.
dc.date.examination	2023-10-11	de
dc.description.abstracteng	Chronic kidney disease is marked by progressive fibrosis and consecutive loss of function – the availability of specific therapies is limited. The bHLH-PAS transcription factor ARNT is able to form homodimeric complexes and to induce the expression of the renoprotective ALK3 in the tubular epithelium by binding to the ALK3 promoter. Pharmacologically, ARNT expression can be induced by a non-immunosuppressive dose of the pharmaceutical FK506 (low-dose) or by the small molecule GPI-1046. In the research literature, the protein phosphatase inhibitor okadaic acid is described as an inducer of ARNT homodimer formation. While the mechanisms of heterodimerisation of ARNT with other bHLH-PAS transcription factors are well known, the mechanism of homodimerization of ARNT is unknown by now. The aim of the thesis was to identify a mechanism of ARNT homodimer formation and to explore therapeutic effects by pharmacological modulation of ARNT homodimers on renal fibrosis in the context of chronic kidney disease. In transgenic HEK293 cells, it was demonstrated that the formation of ARNT homodimers is underlying PP2A inhibition. The specific PP2A inhibitor LB-100 induced the formation of ARNT homodimers in vitro and increased protein stability of Arnt. A transcriptional effect of LB-100 on Arnt expression was not observed by qRT-PCR. Endogenous ARNT homodimers were detected in MCT cells by Blue Native-PAGE and MALDI-TOF analysis. Serine-77 in ARNT was identified by mass spectrometry as a relevant phosphorylation site for the formation of ARNT homodimers. By using an aspartic acid point mutant of ARNT, the specific relevance of phosphorylation at serine-77 on the formation of ARNT homodimers has been proved in transgenic HEK293 cells. The antifibrotic effect of ARNT homodimers was investigated in the mouse model of unilateral ureteral obstruction (UUO). For this study, C57BL/6J wild-type mice were treated with LB-100, FK506, GPI-1046 as a monotherapy or in combination, FK506 + LB-100 and GPI-1046 + LB-100. Combination therapy showed an enhanced formation of ARNT homodimers, an increased expression of the Alk3 and additive antifibrotic effects in murine kidneys. The renoprotective effect of ARNT homodimers could be used in the future for the treatment of chronic kidney disease.	de
dc.contributor.coReferee	Schön, Margarete Prof. Dr.
dc.subject.ger	renale Fibrogenese	de
dc.subject.ger	Homodimerisierung	de
dc.subject.ger	Fibrose	de
dc.subject.ger	Serin-77	de
dc.subject.ger	Tubulusepithelzellen	de
dc.subject.ger	chronische Nierenerkrankung	de
dc.subject.ger	PP2A-Inhibition	de
dc.subject.eng	ARNT	de
dc.subject.eng	fibrosis	de
dc.subject.eng	HIF-1β	de
dc.subject.eng	kidney	de
dc.subject.eng	CKD	de
dc.subject.eng	pSMAD1/5/8	de
dc.subject.eng	aryl hydrocarbon receptor nuclear translocator	de
dc.subject.eng	ALK3 (BMPR1A)	de
dc.subject.eng	homodimerization	de
dc.subject.eng	PP2A	de
dc.subject.eng	Serine-77	de
dc.subject.eng	renal fibrogenesis	de
dc.subject.eng	GPI-1046	de
dc.subject.eng	FK506	de
dc.subject.eng	LB-100	de
dc.subject.eng	bHLH-PAS	de
dc.identifier.urn	urn:nbn:de:gbv:7-ediss-14898-9
dc.affiliation.institute	Medizinische Fakultät	de
dc.subject.gokfull	Innere Medizin - Allgemein- und Gesamtdarstellungen (PPN619875747)	de
dc.description.embargoed	2023-10-19	de
dc.identifier.ppn	1868066606
dc.notes.confirmationsent	Confirmation sent 2023-10-02T19:45:01	de

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