Global gene expression analysis reveals a role for the alpha(1) integrin in renal pathogenesis

Kidney fibrosis is the hallmark of most types of progressive kidney disease , including the genetic disorder Alport's syndrome. We undertook gene expre ssion analysis in Alport's syndrome mouse kidneys using microchip arrays to characterize the development of fibrosis. La addition to matrix and matrix -remodeling genes, consistent with interstitial fibrosis, macrophage-relate d genes show elevated expression levels in Alport's syndrome kidneys. Immun ohistochemical analysis of kidney sections illustrated that macrophages as well as myofibroblasts accumulate in the tubular interstitium. Deletion of alpha (1) 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 beta antagonism, alt hough reducing interstitial fibrosis, does not limit macrophage accumulatio n in the tubular interstitium and disease progression. In this study, we id entified previously overlooked inflammatory events that occur in the tubulo interstitial region. We propose that in addition to the previously suggeste d role for the alpha (1)beta (1) integrin in mesangial expansion and abnorm al laminin deposition, this integrin may be critical for monocyte accumulat ion that, in turn, may lead directly to renal failure. Our gene expression and immunohistochemical data indicate that macrophage accumulation is depen dent on alpha (1) integrin expression on the macrophage cell surface and th at anti-alpha (1) integrin strategies may be employed as therapeutics in th e treatment of chronic inflammatory and fibrotic diseases.