2003
DOI: 10.1016/s0002-9440(10)63486-4
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Abstract: Transforming growth factor-beta1 (TGF-beta1) and the renin-angiotensin-aldosterone system are key mediators in kidney fibrosis. Integrin alphavbeta6, a heterodimeric matrix receptor expressed in epithelia, binds and activates latent TGF-beta1. We used beta6 integrin-null mice (beta6(-/-)) to determine the role of local TGF-beta1 activation in renal fibrosis in the unilateral ureteral obstruction (UUO) model. Obstructed kidneys from beta6(-/-) mice showed less injury than obstructed kidneys from wild-type (WT) … Show more

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Cited by 194 publications
(145 citation statements)
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“…The results of our studies show that antibodymediated blockade of ␣v␤6 can inhibit initiation and early progression of renal fibrosis and suppress its maintenance. Consistent with previous findings from the ␤6-deficient mouse model of unilateral ureteral obstruction, 45 the antifibrotic effects of the ␣v␤6-blocking mAbs observed in our experiments correlated with decreased TGF-␤ activity and expression. Interestingly, the apparent decrease in TGF-␤ and SMA expression after ␣v␤6 mAb treatment occurred not only in the immediate vicinity of ␣v␤6-positive cells but was detectable in relatively distal tissue regions as well.…”
Section: Discussionsupporting
confidence: 93%
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“…The results of our studies show that antibodymediated blockade of ␣v␤6 can inhibit initiation and early progression of renal fibrosis and suppress its maintenance. Consistent with previous findings from the ␤6-deficient mouse model of unilateral ureteral obstruction, 45 the antifibrotic effects of the ␣v␤6-blocking mAbs observed in our experiments correlated with decreased TGF-␤ activity and expression. Interestingly, the apparent decrease in TGF-␤ and SMA expression after ␣v␤6 mAb treatment occurred not only in the immediate vicinity of ␣v␤6-positive cells but was detectable in relatively distal tissue regions as well.…”
Section: Discussionsupporting
confidence: 93%
“…11,17,44 The ␤6 subunit is up-regulated in several forms of renal disease, 10 and its genetic ablation was shown to provide marked protection from injury-induced renal fibrosis in the mouse model of unilateral ureteral obstruction. 45 Similar protection of ␤6-deficient mice from fibrosis has been observed in the bleomycin lung fibrosis model, suggesting that ␣v␤6 can mediate fibrosis in diverse tissues. 17,46 Interestingly, unilateral ureteral obstruction-induced phosphorylation of SMAD2, a central mediator of TGF-␤ signaling was markedly attenuated in the ␤6-deficient kidneys, indicating that ␣v␤6 may operate in vivo as a part of the TGF-␤ regulatory circuitry.…”
Section: Discussionmentioning
confidence: 61%
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“…As described previously (23,26,39), we used immunoblotting with antibodies against phospho-MYPT1 (at Thr-696; 1:2000 dilution; Upstate Biochemistry, Lake Placid, NY) and phospho-Smad2/3 (at Ser-433/435; 1:2000 dilution; Santa Cruz Biotechnology Inc., Santa Cruz, CA) to evaluate Rho-kinase and Smad2/3 activation, respectively. To check for equal loading, membranes were reprobed with an antibody against ␤-actin (1:10,000 dilution; Sigma Chemical).…”
Section: Western Blot Analysismentioning
confidence: 99%
“…48,49 Similarly, aldosterone induces renal PAI-1 expression and fibrosis through a TGF-␤-independent pathway. 50 Several studies have provided evidence for rapid nongenomic effects of aldosterone. 51 For example, aldosterone increases Na/H antiporter activity in VSMCs through a membrane, rather than nuclear receptor.…”
Section: Aldosterone and Cardiovascular Injury In Animal Modelsmentioning
confidence: 99%