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Die Rolle des FK506 bei der Expression des BMP-Rezeptors BMPR1A

dc.contributor.advisorZeisberg, Michael Prof. Dr.
dc.contributor.authorKlöpper, Friederike
dc.titleDie Rolle des FK506 bei der Expression des BMP-Rezeptors BMPR1Ade
dc.title.translatedThe role of FK506 during the expression of the BMP-Receptor BMPR1Ade
dc.contributor.refereeNeeße, Albrecht PD Dr. Dr.
dc.description.abstractengChronic progressive kidney disease (CKD) represents an unsolved worldwide biomedical challenge because of lacking effective therapy strategies. At current state, only BMP7 and its chemically developed analogues reveal a first attempt of a targeted anti-fibrotic therapeutic concept. Nevertheless, progressive kidney fibrosis is associated with the loss of BMP7 while its receptor Bmpr1a, main transductor of BMP7-specific SMAD1/5/8 signaling pathways in tubular epithelial cells (TECs), is induced in different murine models of renal injury. Furthermore, Bmpr1a deletion in mice correlates with an exacerbation of renal destruction. The immunosuppressive calcineurin inhibitor FK506 (Tacrolimus) is the first-line pharmaceutical after renal transplantation. In this regard, extracted data from the web-based disease platform Nephroseq provide evidence for FK506-induced BMPR1A expression in epithelial cell entities. Interestingly, pharmacological low-dose FK506 preconditioning has been known for pre-emptive activation of protective and regenerative pathways to prevent chronic organ failure, while underlying molecular mechanisms of such reno-protection are yet unknown. The aim of this thesis was to determine the hypothesized correlation between FK506 administration and activation of reno-protective BMP7 signaling through transcriptional BMPR1A induction in cultured TECs and mice challenged with the established renal fibrosis mouse model unilateral ureter obstruction (UUO). In line with publicly available datasets, FK506 exposure was associated with Bmpr1a upregulation in TECs and mice, correlated with a consecutive phosphorylation of Smad1/5/8 as characteristics for functional canonical BMP signaling transduction. Interstitial fibrogenesis, tubular atrophy and accumulation of pro-fibrotic markers αSMA, Fsp1 and Collagen-1 were successively reduced in UUO-treated mice receiving FK506. FK506 concentrations in murine whole blood samples were 10-20-fold lower compared to trough levels recommended in renal transplant patient to mediate immunosuppressive calcineurin inhibition. Accordingly, FK506-evoked nephroprotection is not accompanied by a pharmacological calcineurin inhibition and its associated side effects. Elucidating the underlying mechanisms of FK506-mediated BMPR1A induction, results indicated de novo synthesis of an additional transcription factor that binds to the BMPR1A promoter region to initiate receptor induction. By RT2 Profiler PCR array and subsequent sequence alignment, six potential candidate genes with binding motifs in the BMPR1A promoter region were identified. RNAi-mediated gene silencing of identified putative transcription factors was performed, but only when Arnt (Hif-1β) was depleted, FK506 failed to induce Bmpr1a expression. Moreover, Arnt was significantly upregulated upon FK506 exposure both in proximal TECs and in mice challenged with UUO. Subsequently morphometric analyses in a small cohort of transplant recipients with immunosuppressive regimes demonstrated ARNT, BMPR1A and pSMAD1/5/8 accumulation in biopsies of the FK506-treated collective. Ensuing data analysis of human transcriptome array data from Nephroseq database could consolidate generated results in silico in more transplant kidneys. In conclusion, FK506-associated BMPR1A induction could be confirmed as a positive regulator of TEC integrity. The conserved receptor function sensitizes for the anti-fibrotic impact of BMP7 and causes a remission of tubulointerstitial fibrogenesis. Underlying molecular mechanisms includes de novo synthesis of transcription factor ARNT and is also detectable in many other parenchymal organs. These results indicated that pharmacological preconditioning with sub-immunosuppressive doses of FK506 mediates an increased endogenous tissue tolerance and can be postulated as a novel promising therapy strategy to protect chronic organ
dc.contributor.coRefereeMausberg, Rainer Prof. Dr.
dc.subject.gerrenale Fibrogenesede
dc.subject.gerchronisch progrediente Niereninsuffizienzde
dc.subject.gerpharmakologische Präkonditionierungde
dc.subject.gerproximale Tubulusepithelzellende
dc.subject.gerARNT (HIF-1β)de
dc.subject.gerchronisches Organversagende
dc.subject.engrenal fibrogenesisde
dc.subject.engpharmacological preconditioningde
dc.subject.engARNT (HIF-1β)de
dc.subject.engchronic organ failurede
dc.affiliation.instituteMedizinische Fakultätde
dc.subject.gokfullMedizin (PPN619874732)de

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