NDT Advance Access originally published online on February 6, 2007
Nephrology Dialysis Transplantation 2007 22(4):1062-1069; doi:10.1093/ndt/gfl810
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Nephroprotective effect of the HMG-CoA-reductase inhibitor cerivastatin in a mouse model of progressive renal fibrosis in Alport syndrome
1Department of Internal Medicine I, Cologne General Hospital, Merheim Medical Center, 2Department of Anatomy I, University of Cologne, 3Medizinische Poliklinik-Innenstadt, University of Munich, Munich and 4Department of Nephrology & Rheumatology, University of Göttingen, Göttingen, Germany
Correspondence and offprint requests to: PD Dr Oliver Gross, MD, FASN, Department of Nephrology & Rheumatology, University of Göttingen, Robert-Koch-Str. 40, D- 37075 Göttingen, Germany. Email: gross.oliver{at}med.uni-goettingen.de
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Abstract |
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Background. Alport syndrome is caused by mutations in genes encoding for the 
3, 4 or 5 chain of type IV collagen leading to excessive production of fibrotic tissue and end-stage renal failure. HMG-CoA-reductase-inhibitors exhibit pleiotropic effects by which they modulate the production of connective tissue. The aim of this study was to examine the anti-fibrotic effect of the HMG-CoA-reductase-inhibitor, cerivastatin, in COL4A3 knockout mice, an animal model of Alport syndrome with progressive renal fibrosis.
Methods. Forty homozygous COL4A3 knockout mice received cerivastatin, starting 28 or 49 days after birth. Mice were sacrificed at day 52 or 66 after birth. Immunohistochemistry against laminin and fibronectin was performed. Inflammatory cell infiltration was determined by F4/80- and CD3-staining. Myofibroblasts were identified by an -smooth muscle actin staining. Expression of the profibrotic cytokines, TGF-ß1 and CTGF, were determined by immunoblot.
Results. The lifespan of treated COL4A3 knockout mice was increased by 28% compared with untreated animals (71 ± 6 vs 91 ± 9 days, P < 0.01). Early cerivastatin treatment reduced cholesterol levels (113 ± 13 vs 141 ± 19 mmol/l in untreated animals, P < 0.05) and serum urea (164 vs 235 mmol/l, day 66, P < 0.05). Treatment also decreased proteinuria (5.5 vs 12 g/l at day 66, P < 0.05). Deposition of laminin and fibronectin, expression of TGF-ß and CTGF was reduced. Infiltration of T-cells and macrophages as well as myofibroblasts appeared to be reduced in kidneys from cerivastatin-treated mice.
Conclusion. Cerivastatin prolongs the lifespan of COL4A3 knockout mice, reduces proteinuria and delays uraemia. These effects are associated with decreased renal fibrosis and a reduction of inflammatory cell infiltration.
Keywords: alport syndrome; extracellular matrix; renal fibrosis; statins; type IV collagen
Received for publication: 7. 8.06
Accepted in revised form: 12.12.06
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