Neue Therapieansätze für das Alport-Syndrom: Nephroprotektives, antifibrotisches und antiinflammatorisches Potential von Paricalcitol additiv zu Ramipril in einem Mausmodell für progressive Nierenfibrose
New therapeutic approaches for the Alport syndromes disease: nephroprotective, antifibrotic and antiinflammatory effects of Paricalcitol on top of Ramipril in a mouse model for progressie renal fibrosis
Henrik Hiller
Doctoral thesis
Date of Examination:
2014-08-05
Date of issue:
2014-07-25
Advisor:
Gross, Oliver Prof. Dr.
Referee:
Krick, Wolfgang PD Dr.
Referee:
Oppermann, Martin Prof. Dr.
Persistent Address: http://hdl.handle.net/11858/00-1735-0000-0022-5F30-C
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Abstract
English
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 Paricalcitol 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: Paricalcitol alone (PC), Ramipril alone (ACE), Paricalcitol plus Ramipril (ACE + PC) and placebo (PLACEBO). Ramipril therapy was started pre-emptively in week 4. Paricalcitol 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 PC compared to the PLACEBO-group showed no significant difference in survival until renal failure (p=0,083124 ). Mice receiving ACE had a lifespan increased by 40.47% compared to the untreated PLACEBO-group (p=0,005385). Mice receiving ACE + PC had their lifespan increased by 70.5% compared to the PLACEBO-group (p=0,000939 ) and by 21.38% compared to those mice who received ACE alone (p=0,004575 ). Improved renal function in terms of lower blood urea nitrogen (ACE, ACE + PC) and proteinuria (PC, ACE + PC) were found. Also, decreased accumulation of extracellular matrix and renal scarring was found in arms receiving PC and ACE + PC. Conclusion: The combination of Paricalcitol and Ramipril provides promising results for new therapeutic approaches for the Alport syndromes disease. Further investigations are necessary to determine whether the effects of Paricalcitol and Ramipril on mice kidneys tissues apply to humans.
Keywords: alport syndrome; COL4A3; Paricalcitol; Ramipril
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Human- und Zahnmedizin [2270]