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Gene expression analysis in a canine model of X-linked Alport syndrome

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Abstract

Chronic kidney disease (CKD) often culminates in renal failure as a consequence of progressive interstitial fibrosis and is an important cause of illness and death in dogs. Identification of disease biomarkers and gene expression changes will yield valuable information regarding the specific biological pathways involved in disease progression. Toward these goals, gene expression changes in the renal cortex of dogs with X-linked Alport syndrome (XLAS) were examined using microarray technology. Extensive changes in inflammatory, metabolic, immune, and extracellular matrix biology were revealed in affected dogs. Statistical analysis showed 133 genes that were robustly induced or repressed in affected animals relative to age-matched littermates. Altered expression of numerous major histocompatibility complex (MHC) molecules suggests that the immune system plays a significant role in XLAS. Increased expression of COL4A1 and TIMP-1 at the end stage of disease supports the suggestion that expression increases in association with progression of fibrosis and confirms an observation of increased COL4A1 protein expression. Clusterin may function as one of the primary defenses of the renal cortex against progressive injury in dogs with XLAS, as demonstrated here by increased CLU gene expression. Cellular mechanisms that function during excess oxidative stress might also act to deter renal damage, as evidenced by alterations in gene expression of SOD1, ACO1, FDXR, and GPX1. This investigation provides a better understanding of interstitial fibrosis pathogenesis, and potential biomarkers for early detection, factors that are essential to discovering more effective treatments thereby reducing clinical illness and death due to CKD.

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Acknowledgments

This work was supported by grants from the College of Veterinary Medicine Signature Programs Enhancement Initiative and the National Institutes of Health.

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Authors and Affiliations

  1. Department of Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, 77843-4467, USA

    Kimberly A. Greer, Melissa L. Cox & Keith E. Murphy

  2. Lilly Research Laboratories, Eli Lilly and Company, Greenfield, Indiana, 46140, USA

    Marnie A. Higgins, Timothy P. Ryan & Brian R. Berridge

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

    Clifford E. Kashtan

  4. Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, 77843, USA

    George E. Lees

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  1. Kimberly A. Greer
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  2. Marnie A. Higgins
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  3. Melissa L. Cox
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  4. Timothy P. Ryan
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  5. Brian R. Berridge
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  7. George E. Lees
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  8. Keith E. Murphy
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Correspondence to Keith E. Murphy.

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Greer, K.A., Higgins, M.A., Cox, M.L. et al. Gene expression analysis in a canine model of X-linked Alport syndrome. Mamm Genome 17, 976–990 (2006). https://doi.org/10.1007/s00335-005-0179-8

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  • DOI: https://doi.org/10.1007/s00335-005-0179-8

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