Die Effekte von PPARα auf die therapeutische Effektivität von eEOCs beim ischämisch bedingten akuten Nierenversagen von eEOC-behandelten C57BI/6N-Mäusen

The effects of PPARα on eEOC-based therapy in ischemic acute renal failure of eEOC-treated C57BI / 6N mice

by Roman Scheidmann
Doctoral thesis
Date of Examination:2017-01-11
Date of issue:2016-12-21
Advisor:Prof. Dr. Daniel Patschan
Referee:Prof. Dr. Daniel Patschan
Referee:PD Dr. Marco Schroeter
Referee:Prof. Dr. Margarete Schön
Persistent Address: http://dx.doi.org/10.53846/goediss-6054

 

 

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Abstract

English

BACKGROUND: The aim of this work was to investigate consequences of PPARα-activation by fenofibrate and clofibrate, of murine eEOCs in a cell-based therapeutic approach to Acute Renal Failure – AKI.  In the last years it was shown that the renoprotective effect of eEOC-therapy can be improved/modulated by in vitro pre-treatment with 8-O-cAMP, melatonine, angiopoetine-1, angiopetine-2 and Bone Morphogenetic Protein-5. The therapeutic benefit of PPARα-activation in the context of renal and cardiovascular pathology has been demonstrated before. METHODS: Male C57/Bl6N mice, subjected to unilateral renal ischemia (40 min.) and post-uninephrectomy, were systemically injected with 5 × 105 untreated or fenofibrate (FF 50 μM)/clofibrate (CF 1 mM) pretreated syngeneic murine eEOCs. Renal function (serum-creatinine) was analyzed 48 h later. Cellular consequences of eEOC treatment with fibrates (FF 1, 5, 10, 50 μM, CF 1 mM) were evaluated using different in vitro assays (direct cell migration, apoptosis, cellular secretion of vascular endothelial growth factor (VEGF)). RESULTS: Administration of untreated eEOCs did not protect mice from AKI.  Injection of eEOCs treated with FF 50 μm or CF 1 mM did not result in any protection from ischemia-induced renal dysfunction.  In vitro analysis showed reduced cellular secretion of vasoprotective VEGF by CF 1 mM and FF in every concentration except for FF 10 µM. FF 50 µM increased percentages of apoptotic eEOCs, with lower FF concentrations (1, 5, 10 μM) cell survival and migration was increased. CF failed to stimulate migration of cultured cells. CONCLUSION: PPARα-activation using fibrates does not stimulate renoprotective effects of syngeneic murine eEOCs in ischemic AKI, although lower fibrate concentrations significantly activate eEOCs in vitro.
Keywords: Acute Renal Injury; cell-based therapy; fibrate treatment; PPARα; murine eEOCs
 
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