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Petrova D.T.,University Medicine Go Ttingen | Brandhorst G.,University Medicine Go Ttingen | Brehmer F.,University Medicine Go Ttingen | Gross O.,University Hospital Goettingen | And 2 more authors.
Therapeutic Drug Monitoring | Year: 2010

The aim of this study was to elucidate the role of mycophenolic acid (MPA) in cellular pathways of renal fibrosis. Different assays were applied in a renal fibroblast model using COS-7 cells: assays for cell proliferation, scratch wound closure and collagen matrix contraction, gene quantification, and Western blotting. The results indicate that MPA treatment leads to inosine monophosphate dehydrogenase (IMPDH)-dependent inhibition of fibroblast proliferation and wound closure as well as an unexpected IMPDH-independent inhibition of collagen matrix contraction. Interestingly, the IMPDH-independent expression of CTGF after 6 hours incubation with MPA was significantly decreased; however, it became significantly increased and IMPDH-dependent after 24 hours of incubation and longer. Increased mRNA level of COL1A1, TGFβ1, and TNFα was observed after MPA treatment. An unanticipated finding was the divergent and late MPA effect leading to a significant increase of TGFβ1 and CTGF gene expression. The results suggest that long-term incubation with MPA alters signals located upstream of transforming growth factor-β. Furthermore, the protein expression of the apoptotic marker ANXA5 was analyzed in the cell line to exclude apoptosis-related effects using 0.1 to 100 μmol/L MPA. Moreover, in COL4A3-deficient mice treated with different doses of mycophenolate mofetil, we found no significant differences in the gene expression of the same genes supporting the idea of a TGFβ-independent pathway of tubulointerstitial fibrosis in this model for progressive renal disease. In conclusion, the current study indicates that MPA displays IMPDH-dependent and IMPDH-independent effects on renal fibroblast proliferation and function as well as complex signal transduction in COS-7-cells. Alternative inhibitory pathways may contribute to antifibrotic effect of MPA. © 2010 by Lippincott Williams & Wilkins.

To nges L.,University Medicine Go ttingen | To nges L.,Cluster of Excellence 171 Research Center 103 | Szego e .M.,University Medicine Go ttingen | Hause P.,University Medicine Go ttingen | And 13 more authors.
Frontiers in Aging Neuroscience | Year: 2014

The dopaminergic (DAergic) nigrostriatal tract has an intrinsic regenerative capacity which can be impaired in Parkinson's disease (PD). Alpha-synuclein (aSyn) is a major pathogenic component in PD but its impact on DAergic axonal regeneration is largely unknown. In this study, we expressed pathogenic variants of human aSyn by means of recombinant adeno-associated viral vectors in experimental paradigms of DAergic regeneration. In a scratch lesion model in vitro, both aSyn(A30P) and aSyn(A53T) significantly reduced DAergic neurite regeneration and induced loss of TH-immunopositive cells while aSyn(WT) showed only minor cellular neurotoxic effects. The striatal density of TH-immunopositive axons in the striatal 6-OHDA lesion mouse model was attenuated only by aSyn(A30P). However, striatal expression levels of the regeneration marker GAP-43 in TH-immunopositive fibers were reduced by both aSyn(A30P) and aSyn(A53T), but not by aSyn(WT), which was associated with an activation of the ROCK signaling pathway. Nigral DAergic cell loss was only mildly enhanced by additional overexpression of aSyn variants. Our findings indicate that mutations of aSyn have a strong impact on the regenerative capacity of DAergic neurons, which may contribute to their pathogenic effects. © 2014 To¨nges, Szego¨, Hause, Saal, Tatenhorst, Koch, d'Hedouville, Dambeck, Ku¨gler, Dohm, Ba¨hr and Lingor.

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