Global Gene Expression Analysis Reveals a Role for the α1 Integrin in Renal Pathogenesis

Nicole S. Sampson, Sarah T. Ryan, Deborah A. Enke, Dominic E Cosgrove, Victor Koteliansky, Philip Gotwals

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Kidney fibrosis is the hallmark of most types of progressive kidney disease, including the genetic disorder Alport's syndrome. We undertook gene expression analysis in Alport's syndrome mouse kidneys using microchip arrays to characterize the development of fibrosis. In addition to matrix and matrix-remodeling genes, consistent with interstitial fibrosis, macrophage-related genes show elevated expression levels in Alport's syndrome kidneys. Immunohistochemical analysis of kidney sections illustrated that macrophages as well as myofibroblasts accumulate in the tubular interstitium. Deletion of α1 integrin results in decreased accumulation of both myofibroblasts and macrophages in the tubular interstitium in Alport's syndrome mice and delays disease progression. Transforming growth factor β antagonism, although reducing interstitial fibrosis, does not limit macrophage accumulation in the tubular interstitium and disease progression. In this study, we identified previously overlooked inflammatory events that occur in the tubulointerstitial region. We propose that in addition to the previously suggested role for the α1β1 integrin in mesangial expansion and abnormal laminin deposition, this integrin may be critical for monocyte accumulation that, in turn, may lead directly to renal failure. Our gene expression and immunohistochemical data indicate that macrophage accumulation is dependent on α1 integrin expression on the macrophage cell surface and that anti-α1 integrin strategies may be employed as therapeutics in the treatment of chronic inflammatory and fibrotic diseases.

Original languageEnglish (US)
Pages (from-to)34182-34188
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number36
DOIs
Publication statusPublished - Sep 7 2001

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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