Der Einfluss von MicroRNAs auf die Regulation des Ca2+-aktivierten K+-Kanals KCNN4 bei Nierenfibrose

Chronische Nierenkrankungen mit einer Funktionsverschlechterung bis zur terminalen Niereninsuffizienz stellen ein zunehmendes, weltweites Gesundheitsproblem dar. Die gemeinsame pathophysiologische Endstrecke der verschiedenen zugrundliegenden Nierenerkrankungen mündet in einen Fibrosierungsprozess m...

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Bibliographic Details
Main Author: Mann, Christoph
Contributors: Hoyer, Joachim (Prof. Dr. med.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2019
Online Access:PDF Full Text
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Background / Objectives: Activated fibroblasts are key controllers of extracellular matrix turnover in kidney fibrosis, the pathophysiological end stage of chronic kidney disease. The proliferation of activated fibroblasts depends on the expression of the calcium-dependent potassium channel KCNN4. Expression of this ion channel is upregulated in fibrotic kidneys. Genetic and pharmacological blockade of KCNN4 inhibits fibrosis in vitro and in vivo. The mechanisms of upregulation of KCNN4 are poorly understood. Methods: We studied the regulation of KCNN4 and possible involvement of miRNAs in an in-vitro fibrosis model using murine kidney fibroblasts. We tested fibroblast proliferation, channel function, channel expression and expression regulation after FGF-2 stimulation. Results: Proliferation was significantly increased by FGF-2, channel current and expression were almost doubled (+ 91% and +125%, respectively). MiRNA microarray identified upregulation of miRNA-503. In –silico target prediction reveals RAF1-3’UTR harboring a binding site with a high probability of relevant suppression by miR-503. Conclusions: This data show a) a profound upregulation of KCNN4 in stimulated fibroblast and a downregulation of miR-503 b) leads to a hypothesis of regulation of KCNN4-expression via disinhibition of the Ras/Raf/MEK/ERK-cascade by miR-503 targeting RAF1 and c) makes miR-503 (and the miR-424-family) a relevant target for further research regarding diseases relying on increased cell-proliferation like fibrosis or cancer