Angiopoetin-1 im Kontext von EPCs-vermittelter Nephroprotektion nach akuter renaler Ischämie

Angiopoietin-1 in the context of endothelial progenitor cells mediated Nephroprotection after acute renal ischemic

by Nazif Idrizi
Doctoral thesis
Date of Examination:2017-07-25
Date of issue:2017-09-19
Advisor:Prof. Dr. Daniel Patschan
Referee:Prof. Dr. Jörg Wilting
Referee:PD Dr. Frauke Stefanie Czepluch
Referee:Prof. Dr. Rainer Mausberg
Persistent Address: http://dx.doi.org/10.53846/goediss-6493

 

 

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Abstract

English

Aim Acute kidney injury significantly worsens the prognosis of hospitalized patients. Endothelial progenitor cells have been proven as effective tool for AKI prevention in mice. Pharmacological EPC precondition-ing may improve the cells´ renoprotective capacity in this situation. Own previous studies showed that Angiopoietin-1 (Ang-1) pretreatment results in aggravation of post-ischemic kidney dysfunction. The current study was initiated in order to identify the responsible mechanism(s). Methods Cultured, Ang-1 treated murine EPCs were analyzed for production/release of proangiogenic and proin-flammatory mediators, migratory activity, and cell survival, respectively. Finally, male C57/Bl6N mice were injected with either untreated or pretreated (Ang-1) syngeneic murine EPCs (isolated from respec-tive donor mice) after 40 minutes of unilateral renal artery clamping with contralateral nephrectomy. Two days later serum creatinine levels were evaluated. Results Ang-1 significantly accelerated wound closing in EPC cultures as indicated by smaller wound areas at 24 hours after treatment. Ang-1 also stimulated migration of cultured mature endothelial cells in an indirect manner: after artificial wound induction, human umbilical vein endothelial cells were incubated with medium from Ang-1 treated EPCs. This measure significantly accelerated wound closing. Ang-1 did not stimulate VEGF secretion from cultured EPCs. Next, we evaluated whether Ang-1 modulates TGF-β induced apoptosis/necrosis of cultured murine EPCs. Twenty-four hours after a one hour period of Ang-1 treatment, EPCs were analyzed for Annexin V expression and propidiumiodide uptake. Ang-1 signifi-cantly improved cell survival. Finally, we performed a series of in vivo experiments. After a 40 minutes period of ischemia mice were intravenously injected with 0.5 × 106 Ang-1 pretreated cells. Serum creat-inine levels of cell injected animals significantly improved as compared to postischemic mice that did not receive any cells at all or that received untreated cells. It needs to be mentioned that renoprotec-tion exclusively occurred if the cells were not labelled with so-called Celltracker solution prior to in-jection. Conclusions In conclusion, Ang-1 has been identified as new agonist of murine EPCs in ischemic AKI. The deleterious effects on EPCs exclusively occur if the cells are pre-labelled with a certain type of cell dye. Thus, any pharmacological measures intended to modulate / improve EPC competence must be applied with caution.
Keywords: Angiopoietin-1; EPCs; AKI
 
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