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Sirolimus ameliorates the enhanced expression of metalloproteinases in a rat model of autosomal dominant polycystic kidney disease

Berthier, Céline C. ; Wahl, Patricia R. ; Hir, Michel Le ; Marti, Hans-Peter ; Wagner, Ulrich ; Rehrauer, Hubert ; Wüthrich, Rudolf P. ; Serra, Andreas L.

In: Nephrology Dialysis Transplantation, 2008, vol. 23, no. 3, p. 880-889

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    Titel
    • Sirolimus ameliorates the enhanced expression of metalloproteinases in a rat model of autosomal dominant polycystic kidney disease
    Autor
    • Berthier, Céline C.. Institute of Physiology and Center for Integrative Human Physiology, University of Zürich, Zürich
    • Wahl, Patricia R.. Institute of Physiology and Center for Integrative Human Physiology, University of Zürich, Zürich
    • Hir, Michel Le. Institute of Anatomy, University of Zürich, Zürich
    • Marti, Hans-Peter. Clinic and Policlinic for Nephrology, Inselspital, Bern
    • Wagner, Ulrich. Functional Genomics Center, University of Zürich, Zürich
    • Rehrauer, Hubert. Functional Genomics Center, University of Zürich, Zürich
    • Wüthrich, Rudolf P.. Clinic for Nephrology, University Hospital, Zürich
    • Serra, Andreas L.. Clinic for Nephrology, University Hospital, Zürich
    Dokumententyp
    • Postprint
    Sprache
    • Englisch
    Veröffentlicht in
    • Nephrology Dialysis Transplantation, 2008, vol. 23, no. 3, p. 880-889. Oxford University Press
    Andere elektronische Ausgabe
    OAI-PMH-ID
    • oai:doc.rero.ch:304082
    Summary
    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