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Dysregulation of renal MMP-3 and MMP-7 in canine X-linked Alport syndrome

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Abstract

Matrix metalloproteinases (MMPs) play an important regulatory role in many biological and pathological processes and their specific role in Alport syndrome (AS) is not yet clearly defined. In this study, the naturally occurring canine X-linked AS was used to demonstrate a potential role for MMP-3 and MMP-7 in Alport renal pathogenesis. Recently, we demonstrated that the expression of MMP-2, MMP-9 and MMP-14 was upregulated in the renal cortex of dogs with a spontaneous form of XLAS. In the present study, we examined necropsy samples of renal cortex from normal and XLAS dogs for MMP-3 and MMP-7 as they have the potential to activate MMP-2 and MMP-9. Immunohistochemical analysis showed strong immunostaining for both MMP-3 and MMP-7 in the interstitial space of XLAS kidneys, while virtually no immunostaining was observed in similar fields from normal dogs. RT-PCR and casein zymography confirmed that both mRNA transcripts and activities of MMP-3 and MMP-7 are elevated in XLAS kidneys. The induction of these MMPs likely contributes to tissue destruction associated with the fibrogenic process, while augmenting the activation of MMP-2 and MMP-9 by MMP-3 and MMP-7 in XLAS. Thus, these data further implicate a role for the MMPs in progressive renal pathogenesis associated with AS.

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Acknowledgements

This research was supported in part by NIH R01 DK55000 to D.C., NIH R01 DK57676 to C.E.K., and the tobacco settlement fund from the State of Nebraska. We thank Q. Kong for her help in preparing the histograms and statistical analysis, and Rene Rodgers for sequence analysis. We also thank John (Skip) Kennedy for help in figure preparation.

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Authors and Affiliations

  1. Department of Genetics, Boys Town National Research Hospital, Omaha, NE 68131, USA

    Velidi H. Rao, Duane C. Delimont, Daniel T. Meehan & Gautam Bhattacharya

  2. Texas A & M University, College Station, TX 77843, USA

    George E. Lees

  3. Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN 55455, USA

    Clifford E. Kashtan

  4. Department of Pathology, University of Nebraska Medical Center, Omaha, NE 68198, USA

    Rakesh Singh

  5. Greenfield Lilly Research Laboratories, Greenfield, IN 46140, USA

    Brian R. Berridge

  6. Gene Expression Laboratory, Department of Genetics, Boys Town National Research Hospital, Omaha, NE 68131, USA

    Dominic Cosgrove

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  1. Velidi H. Rao
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  2. George E. Lees
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  9. Dominic Cosgrove
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Correspondence to Dominic Cosgrove.

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Rao, V.H., Lees, G.E., Kashtan, C.E. et al. Dysregulation of renal MMP-3 and MMP-7 in canine X-linked Alport syndrome. Pediatr Nephrol 20, 732–739 (2005). https://doi.org/10.1007/s00467-004-1805-5

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  • DOI: https://doi.org/10.1007/s00467-004-1805-5

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