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Molecular Medicine

, Volume 14, Issue 5–6, pp 276–285 | Cite as

Molecular Pathways Involved in Loss of Kidney Graft Function with Tubular Atrophy and Interstitial Fibrosis

  • Daniel G. Maluf
  • Valeria R. Mas
  • Kellie J. Archer
  • Kenneth Yanek
  • Eric M. Gibney
  • Anne L. King
  • Adrian Cotterell
  • Robert A. Fisher
  • Marc P. Posner
Research Article

Abstract

Loss of kidney graft function with tubular atrophy (TA) and interstitial fibrosis (IF) causes most kidney allograft losses. We aimed to identify the molecular pathways involved in IF/TA progression. Kidney biopsies from normal kidneys (n = 24), normal allografts (n = 6), and allografts with IF/TA (n = 17) were analyzed using high-density oligonucleotide microarray. Probe set level tests of hypotheses tests were conducted to identify genes with a significant trend in gene expression across the three groups using Jonckheere-Terpstra test for trend. Interaction networks and functional analysis were used. An unsupervised hierarchical clustering analysis showed that all the IF/TA samples were associated with high correlation. Gene ontology classified the differentially expressed genes as related to immune response, inflammation, and matrix deposition. Chemokines (CX), CX receptor (for example, CCL5 and CXCR4), interleukin, and interleukin receptor (for example, IL-8 and IL10RA) genes were overexpressed in IF/TA samples compared with normal allografts and normal kidneys. Genes involved in apoptosis (for example, CASP4 and CASP5) were importantly overexpressed in IF/TA. Genes related to angiogenesis (for example, ANGPTL3, ANGPT2, and VEGF) were downregulated in IF/TA. Genes related to matrix production-deposition were upregulated in IF/TA. A distinctive gene expression pattern was observed in IF/TA samples compared with normal allografts and normal kidneys. We were able to establish a trend in gene expression for genes involved in different pathways among the studied groups. The top-scored networks were related to immune response, inflammation, and cell-to-cell interaction, showing the importance of chronic inflammation in progressive graft deterioration.

Notes

Acknowledgments

This study has been supported by a grant from ROCHE Laboratories Investigator Initiated Research Program.

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Copyright information

© Feinstein Institute for Medical Research 2008

Authors and Affiliations

  • Daniel G. Maluf
    • 1
  • Valeria R. Mas
    • 1
    • 2
  • Kellie J. Archer
    • 3
    • 4
  • Kenneth Yanek
    • 1
  • Eric M. Gibney
    • 5
  • Anne L. King
    • 5
  • Adrian Cotterell
    • 1
  • Robert A. Fisher
    • 1
  • Marc P. Posner
    • 1
  1. 1.Department of Surgery, Division of Transplant, West Hospital 9th floorVirginia Commonwealth UniversityRichmondUSA
  2. 2.Department of Pathology, Division of TransplantVirginia Commonwealth UniversityRichmondUSA
  3. 3.Department of Biostastistics, Division of TransplantVirginia Commonwealth UniversityRichmondUSA
  4. 4.Center for the Study of Biological ComplexityVirginia Commonwealth UniversityRichmondUSA
  5. 5.Division of NephrologyVirginia Commonwealth UniversityRichmondUSA

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