Nierenschützende Wirkung von Calcitriol additiv zu Ramipril auf die Nierenfibrose im AlportMaus-Modell

Nephroprotective effects of Calcitriol additive to ramipril on renal fibrosis in Alport mice

von Ayse Ciner
Dissertation
Datum der mündl. Prüfung:2016-03-16
Erschienen:2016-03-01
Betreuer:Prof. Dr. Oliver Gross
Gutachter:Dr. Wolfgang Pd Krick
Gutachter:Prof. Dr. Margarete Schön
Zum Verlinken/Zitieren: http://dx.doi.org/10.53846/goediss-5516

 

 

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Englisch

Background: Alport syndrome (AS) is a hereditary, progressive, glomerular nephritis that leads to end-stage renal disease in young adult life. AS is a rare and presently uncurable condition; available treatments tackle symptoms only. Considering the high burden of the disease on individuals, their families and society, establishing new therapies is a pressing need. Aims: this study aimed to estimate the nephroprotective effect of Calcitriol alone and in combination with Ramipril on COL4A3-knockout mice. Methods: The COL4A3-knockout mouse which develops a progressive glomerulonephritis similar to the human Alport syndromes disease served as animal model. One hundred and sixteen mice were included in this study. Eighty four mice underwent a CLO4A3-knockout while the remaining thirty two were wild-type mice and served as control group. The COL4A3-knockout mice were divided into four treatment arms: Calcitriol alone (C), Ramipril alone (ACE), Calcitriol plus Ramipril (ACE + C) and placebo (PLACEBO). Ramipril therapy was started pre-emptively in week 4. Calcitriol therapy was initiated in six week old animals with ongoing renal fibrosis and lasted for six weeks. Four to six animals from each arm were sacrificed after 9.5 weeks to investigate their kindney functions using immunohistological and westernblot techniques. Blood samples were taken to determine blood urea nitrogen levels. Survival until end-stage renal failure was measured. Urin samples were taken from the remaining living animals at weeks 4.5, 6, 7.5 and 9.5 and were screened for proteinuria. Findings: Mice receiving C compared to the PLACEBO-group showed no significant difference in survival until renal failure. Mice receiving ACE had a lifespan increased by 53% compared to the untreated PLACEBO-group (p=0,001). Mice receiving ACE + C had their lifespan increased by 70% compared to the PLACEBO-group (p=0,0001 ) and by 10% compared to those mice who received ACE alone wich ist statistical not signifikant. An Improved renal function in terms of proteinuria (C, ACE + C) was found. Also, decreased accumulation of extracellular matrix and renal scarring was found in arms receiving C and ACE + C. Conclusion: Substituting Calcitriol as the active form of vitamin D in COL4A3-knockout mice can have a beneficiary effect on the progression of their chronic renal failure. Further investigations are necessary to determine whether the positive effects of Calcitriol on mice kidneys tissues apply to humans.
Keywords: alport syndrome; COL4A3; Calcitriol; Ramipril
Schlagwörter: alport syndrome; COL4A3; Calcitriol; Ramipril
 
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