Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome


Gross, O., Beirowski, B., Koepke, M.L., Kuck, J., Reiner, M., Addicks, K., Smyth, N., Schulze-Lohoff, E. and Weber, M. (2003) Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome. Kidney International, 63, (2), 438-446. (doi:10.1046/j.1523-1755.2003.00779.x).

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Description/Abstract

Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome.

Background
Alport syndrome (AS) is a common hereditary cause of end-stage renal failure in adolescence due to defects in type IV collagen genes. Molecular genetics allows early diagnosis, however, no preventive strategy can be offered. Using the COL4A3 -/- mouse, an animal model for human AS, we evaluated therapy with ramipril in mice.

Methods
One hundred and twenty-two Alport-mice were treated with 10 mg/kg/day ramipril added to drinking water. Proteinuria, serum-urea and lifespan were monitored. Renal matrix was characterized by immunohistochemistry, light- and electron microscopy, and Western blot.

Results
Untreated COL4A3 -/- mice died from renal failure after 71 plusminus 6 days. Early therapy starting at four weeks of age and continuing to death delayed onset and reduced the extent of proteinuria. Uremia was postponed by three weeks in treated animals. Lifespan increased by more than 100% to 150 plusminus 21 days (P < 0.01). In parallel, decreased deposition of extracellular matrix and lessened interstitial fibrosis as well as reduced amounts of renal transforming growth factor-beta1 (TGF-beta1) could be demonstrated. Late therapy starting at seven weeks decreased proteinuria, however, lifespan did not increase significantly.

Conclusions
The results indicate an antiproteinuric and antifibrotic nephroprotective effect of ramipril in COL4A3 -/- mice is mediated by down-regulation of TGF-beta1. This effect in mice is enhanced by initiation of therapy during pre-symptomatic disease. The data in COL4A3 -/- mice as an animal-model for Alport syndrome suggest that ramipril might as well delay renal failure in humans with AS. Early diagnosis and preemptive treatment also may be crucial in humans.

Item Type: Article
ISSNs: 0085-2538 (print)
Related URLs:
Keywords: hereditary kidney disease, type IV collagen, ACE-inhibitors, extracellular matrix, treatment of renal disease, ramipril
Subjects: Q Science > Q Science (General)
R Medicine > R Medicine (General)
Divisions: University Structure - Pre August 2011 > School of Biological Sciences
ePrint ID: 56334
Date Deposited: 08 Aug 2008
Last Modified: 27 Mar 2014 18:39
URI: http://eprints.soton.ac.uk/id/eprint/56334

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