NDT Advance Access originally published online on November 27, 2007
Nephrology Dialysis Transplantation 2008 23(3):880-889; doi:10.1093/ndt/gfm697
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Sirolimus ameliorates the enhanced expression of metalloproteinases in a rat model of autosomal dominant polycystic kidney disease
1 Institute of Physiology and Center for Integrative Human Physiology, University of Zürich, Zürich 2 Institute of Anatomy, University of Zürich, Zürich 3 Clinic and Policlinic for Nephrology, Inselspital, Bern 4 Functional Genomics Center, University of Zürich, Zürich 5 Clinic for Nephrology, University Hospital, Zürich
Andreas L. Serra, MD, Clinic for Nephrology, University Hospital Zürich, Rämistrasse100–8091 Zürich, Switzerland. Tel: +41442553384; Fax: +41442554593; E-mail: andreas.serra{at}usz.ch
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Abstract |
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Background. Remodelling of matrix and tubular basement membranes (TBM) is a characteristic of polycystic kidney disease. We hypothesized that matrix and TBM degradation by metalloproteinases (MMPs) could promote cyst formation. We therefore investigated the renal expression of MMPs in the Han:SPRD rat model of autosomal dominant polycystic kidney disease (ADPKD) and examined the effect of sirolimus treatment on MMPs.
Methods. 5-week-old male heterozygous (Cy/+) and wild-type normal (+/+) rats were treated with sirolimus (2 mg/kg/day) through drinking water for 3 months.
Results. The mRNA and protein levels of MMP-2 and MMP-14 were markedly increased in the kidneys of heterozygous Cy/+ animals compared to wild-type +/+ as shown by RT-PCR and Western blot analyses for MMP-2 and MMP-14, and by zymography for MMP-2. Strong MMP-2 expression was detected by immunoperoxidase staining in cystic epithelial cells that also displayed an altered, thickened TBM. Tissue inhibitor of metalloproteinases-2 (TIMP-2) expression was not changed in Cy/+ kidneys. Sirolimus treatment leads to decreased protein expression of MMP-2 and MMP-14 in Cy/+, whereas MMP-2 and MMP-14 mRNA levels and TIMP-2 protein levels were not affected by sirolimus.
Conclusion. In summary, in kidneys of the Han:SPRD rat model of ADPKD, there is a marked upregulation of MMP-2 and MMP-14. Sirolimus treatment was associated with a marked improvement of MMP-2 and MMP-14 overexpression, and this correlated also with less matrix and TBM alterations and milder cystic disease.
Keywords: matrix metalloproteinases (MMPs); polycystic kidney disease (PKD); sirolimus; tissue inhibitors of metalloproteinases (TIMPs)
* Both authors contributed equally.
Received for publication: 1. 5.07
Accepted in revised form: 7. 9.07
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