Complementinhibition mittels Eculizumab verstärkt den nephroprotektiven Effekt von ACE-Inhibitoren in einem COL4A3-Knockout-Mausmodell für das Alport-Syndrom

Complement inhibition via eculizumab enhances nephroprotective effect of ACE inhibitors in a COL4A3 knockout mouse model for Alport Syndrom

by Jakob Valk
Doctoral thesis
Date of Examination:2020-02-19
Date of issue:2020-02-14
Advisor:Prof. Dr. Oliver Gross
Referee:Prof. Dr. Martin Oppermann
Referee:Prof. Dr. Margarete Schön
Persistent Address: http://dx.doi.org/10.53846/goediss-7857

 

 

Files in this item

Name:Dissertation fertig EDISS abgabe..pdf
Size:2.41Mb
Format:PDF

The following license files are associated with this item:

Abstract

English

Alport syndrome (AS) is a hereditary disease associated with progressive renal failure and kidney fibrosis. The disease is caused by mutations in genes encoding for either the α3, 4 or 5 chain of type IV collagen, which lead to changes in the glomerular basement membrane and the podocytes. In the course of the disease, these changes cause haematuria, proteinuria and progressive renal fibrosis leading to end stage renal failure. In this study the antifibrotic nephroprotective effects of eculizumab alone and in combination with the standard ACEI therapy in COL4A3 knockout mice (Col4A3 -/-), which serve as animal model for Alport Syndrom, was tested. 64 of the knockout mice were treated in 4 groups: with Eculizumab (ECU) 40 mg/kg, or vehicle 0.1 ml s.c 3x/wk, (ACE) with Ramipril 10 mg/kg/day p.o., and (ECU+ACE) with Eculizumab plus Ramipril. Ramipril and Eculizumab monotherapy started before the start of proteinuria in week 4. In the ECU+ACEI-group, Ramipril was started in week 4 and ECU was applied in 6 week old animals already showing renal damage and lasted for 6 weeks. Three mice of each group were sacrificed after 7.5 and three after 9.5 weeks. The kidneys were investigated using histological, immunohistological and Western blot techniques. Survival until end stage renal failure was determined in the remaining 8 mice. Additionally the urine of 4, 6, 7.5 and 9 weeks old mice were analyzed for proteinuria marker proteins. ECU-monotherapy had a positive effect on accumulation of extracellular matrix and renal scarring, even stronger than the well established ACEI-monotherapy in 7,5 w old COL4A3 -/- mice. Dual therapy with ACEI and ECU showed the strongest effect in immunehistochemistry. In contrast to the positive effects of the ECU-monotherapy on the accumulation of extracellular matrix and renal scarring, the effects on the overall survival were less impressive. ECU+ACEI, but not the ECU-monotherapy prolonged overall lifespan by 9% compared to ACEI-monotherapy. The effect on the proteinuria also was mild showing a beneficial effect of eculizumab in mono therapy only for low molecular weight proteins. In COL4A3 -/- mice, the complement-inhibitor Eculizumab in combination with ACE-inhibition reduces fibrosis and prolongs survival compared to ACEI monotherapy. Despite the late onset of therapy, this nephroprotective and antifibrotic effect may still be beneficial as on top medication on ACEI. This effect might also be applicable also to other chronic progressive kidney disease.
Keywords: Complement inhibition; Alport Syndrom; COL4A3; eculizumab
 
Statistik