Prävention des Nierenversagens und der Nierenfibrose bei hereditären Erkrankungen der glomerulären Basalmembran (Alport-Syndrom) bei COL4A3-Knockout-Mäusen mit dem Reninantagonisten Aliskiren

Prävention des Nierenversagens und der Nierenfibrose bei hereditären Erkrankungen der glomerulären Basalmembran (Alport-Syndrom) bei COL4A3-Knockout-Mäusen mit dem Reninantagonisten Aliskiren

Prevention of renal failure and renal fibrosis in hereditary diseases of glomerular basement membrane (Alport-Syndrome) in COL4A3 knockout mice with Aliskiren a direct renin inhibitor

Stephanie Theisen

Doctoral thesis

Date of Examination: 2012-06-04

Date of issue: 2012-05-31

Advisor: Gross, Oliver Prof. Dr.

Referee: Gross, Oliver Prof. Dr.

Referee: Krick, Wolfgang PD Dr.

Referee: Virsik-Köpp, Patricia Prof. Dr.

Persistent Address: http://hdl.handle.net/11858/00-1735-0000-000D-EFBF-4

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Abstract

English

The nephroprotectiv properties of the direct renin inhibitor Aliskiren in homozygote COL4A3 knockout mice were analysed in this paper. Consistent with the human disease Alport Syndrome, the mouse model shows the same pathogenesis and course of disease. Alport Syndrome is a progressive hereditary glomerulonephritis with hematuria and proteinuria. Other extrarenal symptoms are sensorineural deafness and ocular features. Finally the glomerulonephritis leads to end-stage renal failure. The main cause of the disease are mutations in the collagen type IV genes. The aim of this study was to review whether Aliskiren has the ability to prevent end-stage renal failure in Alport Syndrome in a protective manner. A total of 39 mice were examined for survival, histology and proteinuria. Untreated homozygote COL4A3 knockout mice were used for control group. The survival was analysed in a Kaplan-Meier curve and the histological specimens were evaluated by a Score. For urine analysis protein samples were made and reviewed with SDS-Page. Indeed a beneficial trend was observed by treatment with Aliskiren. In particular the survival findings showed a significant advantage of the direct renin inhibitor. Findings in histology and proteinuria were less convincing because of a lacking number of cases. Nevertheless even in histology nephrosclerosis was less pronounced in the therapy group than in the control group. As well the therapy group leads to a reduction of macroproteinuria. To sum up, one could say that renin inhibition by Aliskiren, the interference into the RAAS, leads to a prolongation of survival in the investigated animal model. It seems that Aliskiren has the opportunity to delay end-stage renal failure and displays a potential therapy approach. At present Aliskiren is still not accepted as first-line-therapy in chronic nephropathy or Alport Syndrome. It has to be proved alongside medicaments like ACE-Inhibitors or AT1-Antagonists in future studies. The pathogenic development up to end-stage renal disease in Alport Syndrome remains still unclear. To get a better understanding of the disease it is important to have a better knowledge about the pathogenesis. In fact this can lead to more efficient therapies or even stabilize proven therapies. The significance of RAAS in the pathogenesis of Alport Syndrome was presented in the present paper and as well in papers with other RAAS Blocker in humans and animal models. Currently transplantation is the only real curative option. It's a wearing procedure and complications like graft loss are quite possible. This shows the necessity to establish more sufficient therapies with fewer adverse events. Blocking the RAAS could be a good alternative to transplantation. Possible are monotherapies with ACE-Inhibitors, AT1-Antagonists, Aldosteron-Antagonists and the direct renin inhibitor Aliskiren as well as a combination of the medicaments mentioned above in different variation. We expect new findings from future studies like the Alport-Register, where properties of ACE-Inhibitors are discovered in childhood.

Keywords: direct renin inhibitor Aliskiren; COL4A3 knockout mice; Alport Syndrome; collagen type IV; end-stage renal failure; chronic nephropathie; RAAS; RAAS-Blocker; ACE-Inhibitors; AT1-Antagonists

Other Languages

In der vorliegenden Arbeit wurde der Renininhibitor Aliskiren bei homozygoten Col4A3-Knockout-Mäusen auf seine nephroprotektive Wirkung hin untersucht.

Schlagwörter: Renininhibitor Aliskiren; Col4A3-Knockout-Mäuse; Alport-Syndrom; Kollagen Typ IV; terminalen Nierenversagens; chronische Nierenerkrankungen; RAAS; RAAS-Blockade; ACE-Hemmer; AT1-Antagonisten