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 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 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, 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 alpha(1)beta(1) 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 alpha(1) integrin expression on the macrophage cell surface and that anti-alpha(1) integrin strategies may be employed as therapeutics in the treatment of chronic inflammatory and fibrotic diseases.
Sampson
N S
NS
Biogen, Inc., Cambridge, Massachusetts 02142, USA.
Ryan
S T
ST
Enke
D A
DA
Cosgrove
D
D
Koteliansky
V
V
Gotwals
P
P
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D002874:Chromosome Mapping; D004195:Disease Models, Animal; D015536:Down-Regulation; D005355:Fibrosis; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics; D039423:Integrin alpha1; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007797:Laminin / Q000378:metabolism; D051379:Mice; D009394:Nephritis, Hereditary / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D018075:RNA, Complementary / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation
D015703:Antigens, CD; D039423:Integrin alpha1; D007797:Laminin; D018075:RNA, Complementary; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta