Transforming Growth Factor-β-Dependent and -Independent Pathways of Induction of Tubulointerstitial Fibrosis in β6−/− Mice

Ma, Lijun; Yang, Haichun; Gaspert, Ariana; Carlesso, G; Barty, Melissa M.; Davidson, Jeffrey M.; Sheppard, Dean; Fogo, Agnes B.

doi:10.1016/s0002-9440(10)63486-4

Cited by 200 publications

(147 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%

“…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%

“…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. 45 Previous studies with ␤6 knockout mice have provided evidence that ␣v␤6 can play a role in the initiation of fibrosis, suggesting this integrin as a potential novel therapeutic target. We sought to determine whether pharmacological inhibition of ␣v␤6 function with blocking mAbs could attenuate renal fibrosis in Col4A3 Ϫ/Ϫ mice, an animal model of the autosomal recessive Alport syndrome.…”

Section: Discussionmentioning

confidence: 99%

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αvβ6 Integrin Regulates Renal Fibrosis and Inflammation in Alport Mouse

Hahm

Lukashev

Luo

et al. 2007

The American Journal of Pathology

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178

132

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The transforming growth factor (TGF)-␤-inducible integrin ␣v␤6 is preferentially expressed at sites of epithelial remodeling and has been shown to bind and activate latent precursor TGF-␤. Herein , we show that ␣v␤6 is overexpressed in human kidney epithelium in membranous glomerulonephritis , diabetes mellitus , IgA nephropathy , Goodpasture's syndrome , and Alport syndrome renal epithelium. To assess the potential regulatory role of ␣v␤6 in renal disease , we studied the effects of functionblocking ␣v␤6 monoclonal antibodies (mAbs) and genetic ablation of the ␤6 subunit on kidney fibrosis in Col4A3 ؊/؊ mice , a mouse model of Alport syndrome. Expression of ␣v␤6 in Alport mouse kidneys was observed primarily in cortical tubular epithelial cells and in correlation with the progression of fibrosis. Treatment with ␣v␤6-blocking mAbs inhibited accumulation of activated fibroblasts and deposition of interstitial collagen matrix. Similar inhibition of renal fibrosis was observed in ␤6-deficient Alport mice. Transcript profiling of kidney tissues showed that ␣v␤6-blocking mAbs significantly inhibited disease-associated changes in expression of fibrotic and inflammatory mediators. Similar patterns of transcript modulation were produced with recombinant soluble TGF-␤ RII treatment , suggesting shared regulatory functions of ␣v␤6 and TGF-␤. These findings demonstrate that ␣v␤6 can contribute to the regulation of renal fibrosis and suggest this integrin as a potential therapeutic target.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

αvβ6 Integrin Regulates Renal Fibrosis and Inflammation in Alport Mouse

Hahm

Lukashev

Luo

et al. 2007

The American Journal of Pathology

Self Cite

178

132

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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%

Involvements of Rho-Kinase and TGF-β Pathways in Aldosterone-Induced Renal Injury

Sun

Kohno

Guo

et al. 2006

Journal of the American Society of Nephrology

110

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Recent studies have suggested a role for aldosterone in the pathogenesis of renal injury. This study investigated the potential contributions of Rho-kinase and TGF-␤ pathways to aldosterone-induced renal injury. Rats were uninephrectomized and then treated for 5 wk with 1% NaCl in a drinking solution and one of the following: Vehicle (2% ethanol, subcutaneously; n ‫؍‬ 9); aldosterone (0.75 g/h, subcutaneously; n ‫؍‬ 9); or aldosterone ؉ fasudil, a specific Rho-kinase inhibitor (10 mg/kg per d, subcutaneously; n ‫؍‬ 8). Phosphorylation of myosin phosphate target subunit-1 (MYPT1) and Smad2/3 in renal cortical tissue was measured by Western blotting with anti-phospho MYPT1 and Smad2/3 antibodies, respectively. Rats that received aldosterone infusion exhibited hypertension and severe renal injury characterized by proteinuria, glomerular sclerosis, and tubulointerstitial fibrosis with increases in ␣-smooth muscle actin staining and numbers of monocytes/macrophages in the interstitium. Renal cortical mRNA levels of types I and III collagen, TGF-␤, connective tissue growth factor, and monocyte chemoattractant protein-1 as well as Smad2/3 phosphorylation were significantly increased in rats that received aldosterone infusion. All of these changes were associated with an increase in renal tissue MYPT1 phosphorylation. Treatment with fasudil did not alter BP but significantly ameliorated proteinuria and renal injury in rats that received aldosterone infusion. Severe glomerular injury and interstitial fibrosis were observed in rats that were treated long term with aldosterone/ salt (3,4). Moreover, exogenous infusion of aldosterone reversed the renoprotective effects of angiotensin II blockade in remnant kidney hypertensive rats (5). In stroke-prone spontaneously hypertensive rats (6); Dahl salt-sensitive hypertensive rats (7); and rats that were treated with angiotensin II and a nitric oxide synthase inhibitor (8), cyclosporine A (9), or radiation (10), treatment with mineralocorticoid receptor (MR) antagonists had no effect on systemic BP (SBP) but significantly ameliorated renal injury. In patients with chronic renal failure (11) and early diabetic nephropathy (12), the addition of MR antagonists to angiotensin-converting enzyme (ACE) inhibitors had no hemodynamic effects but markedly reduced proteinuria. Further studies also showed that monotherapy with MR antagonists was more effective than ACE inhibitors in reducing proteinuria in hypertensive patients (13,14). We recently found that aldosterone stimulates reactive oxygen species production (15) and induces cell proliferation (16) or deformation (16) in cultured glomerular mesangial cells. In addition, aldosterone stimulated collagen synthesis in cultured renal fibroblasts (17). Collectively, these data suggest that aldosterone has deleterious effects on the kidney that cannot be explained simply by BP changes. However, the precise mechanisms that are responsible for aldosterone-induced renal injury remain undetermined.Rho-kinase, an effector of the small G protein ...

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“…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%

Eplerenone

Brown

2003

Circulation

138

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Abstract-Data from animal studies and clinical trials indicate that aldosterone causes cardiovascular and renal injury through mineralocorticoid receptor-dependent mechanisms. However, although aldosterone receptor antagonism reduces mortality in patients with congestive heart failure, the progestational and antiandrogenic side effects of the nonspecific aldosterone receptor antagonist, spironolactone, have limited its usefulness in the treatment of hypertension. This review provides an overview of the pharmacology, efficacy, and safety of a new, more selective aldosterone receptor antagonist, eplerenone, in the context of emerging concepts of the role of aldosterone in cardiovascular toxicity. Key Words: aldosterone Ⅲ receptors Ⅲ cardiovascular disease Ⅲ hypertension Ⅲ pharmacology T he renin-angiotensin-aldosterone system (RAAS) plays an integral role in cardiovascular homeostasis through its effects on vascular tone and volume. Activation of the RAAS is associated with an increased risk of ischemic cardiovascular events, independent of effects on blood pressure, 1 whereas interruption of the RAAS by angiotensin-converting enzyme (ACE) inhibition or angiotensin type 1 receptor (AT 1 R) blockade reduces cardiovascular mortality 2,3 and slows the progression of renal disease. 4,5 Drugs that interrupt the RAAS reduce the risk of cardiovascular events, preventing the effects of angiotensin (Ang) II on cellular growth and proliferation, 6 on vascular superoxide radical formation, 7 and on thrombotic pathways. 8 Ang II also stimulates the synthesis of the mineralocorticoid aldosterone, and emerging data indicate that aldosterone plays an independent role in vascular toxicity and fibrosis. For example, molecular studies suggest that aldosterone may be produced locally in vascular tissue. 9 Aldosterone causes myocardial and aortic fibrosis and nephrosclerosis in animal models, whereas aldosterone receptor antagonism reverses these processes. 10 -15 In humans, elevated plasma aldosterone concentrations are associated with endothelial dysfunction, myocardial infarction, left ventricular hypertrophy, and death. 16 -18 Although ACE inhibition and AT 1 receptor antagonism initially reduce aldosterone concentrations, circulating concentrations of this hormone return to baseline levels with chronic therapy. 19,20 Coadministration of the aldosterone receptor antagonist, spironolactone, enhances the beneficial effect of ACE inhibition on mortality in patients with congestive heart failure. 21 However, although administration of spironolactone reduces mortality in patients with congestive heart failure, the progestational and antiandrogenic side effects of this nonspecific aldosterone receptor antagonist have limited its usefulness in the treatment of hypertension predominantly to the treatment of patients with primary hyperaldosteronism. The Food and Drug Administration (FDA) has approved a new, more selective aldosterone receptor antagonist, eplerenone, for the treatment of hypertension. This review provides an overview of...

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Transforming Growth Factor-β-Dependent and -Independent Pathways of Induction of Tubulointerstitial Fibrosis in β6−/− Mice

Cited by 200 publications

References 36 publications

αvβ6 Integrin Regulates Renal Fibrosis and Inflammation in Alport Mouse

αvβ6 Integrin Regulates Renal Fibrosis and Inflammation in Alport Mouse

Involvements of Rho-Kinase and TGF-β Pathways in Aldosterone-Induced Renal Injury

Eplerenone

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