Blockade of TGF-β action ameliorates renal dysfunction and histologic progression in anti-GBM nephritis

Zhou, Aihua; Ueno, Hikaru; Shimomura, M; Tanaka, Ryojiro; Shirakawa, Toshiro; Nakamura, Hajime; Matsuo, Masafumi; Iijima, Kazumoto

doi:10.1046/j.1523-1755.2003.00045.x

Cited by 45 publications

(36 citation statements)

References 32 publications

(4 reference statements)

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“…The present study has answered all these questions by adenovirus-mediated expression of a soluble TGF-b receptor that can abolish TGF-b signaling. [14][15][16] It is now recognized that repeated episodes of acute pancreatitis can lead to increasing residual damage to the gland, eventually resulting in chronic pancreatitis (the necrosis-fibrosis sequence). 17,34,35 Therefore, we chose this chronic pancreatitis model induced by repeated acute pancreatitis in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…In previous studies, we showed that serum level of this soluble receptor reached a peak value at 5-7 days after the injection and gradually declined thereafter, but that it was still detectable even at 21 days after injection. [14][15][16] Animals Male BALB/c mice (Kyudo Co., Kumamoto, Japan) weighing 20-22 g were used. The animals were kept in a 12 h light/dark cycle with free access to water and a standard mouse chow.…”

Section: Replication-defective Recombinant Adenovirusesmentioning

confidence: 99%

“…14,15 This soluble receptor is secreted from cells infected with AdTb-ExR into the circulating blood, reaches remote area, binds to TGF-b, and thereby inhibits its action. [14][15][16] The use of AdTb-ExR can block the action of TGF-b in organs where direct gene transfer seems restrained. As an experimental pancreatic fibrosis model, we used mice treated with repeated cerulein injections, 17,18 an established animal model of chronic pancreatic injury and pancreatic fibrosis with a pathophysiology that closely resembles that of human chronic pancreatitis.…”

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confidence: 99%

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Inhibition of transforming growth factor β decreases pancreatic fibrosis and protects the pancreas against chronic injury in mice

Nagashio

Ueno

Imamura

et al. 2004

Laboratory Investigation

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Transforming growth factor-b (TGF-b) is an important cytokine in the fibrogenesis in many organs, including the pancreas. Using an adenoviral vector expressing the entire extracellular domain of type II human TGF-b receptor (AdTb-ExR), we investigated whether inhibition of TGF-b action is effective against persistent pancreatic fibrosis, and whether it exerts a beneficial effect on the pancreas in the process of chronic injury. To induce chronic pancreatic injury and pancreatic fibrosis, mice were subjected to three episodes of acute pancreatitis induced by six intraperitoneal injections of 50 lg/kg body weight cerulein at hourly intervals, per week for 3 consecutive weeks. Mice were infected once with AdTb-ExR, or with a control adenoviral vector expressing bacterial b-galactosidase (AdLacZ). Pancreatic fibrosis was evaluated by histology and hydroxyproline content. Activation of pancreatic stellate cells (PSCs) was assessed by immunostaining for a-smooth muscle actin. Apoptosis and proliferation of acinar cells were assessed by immunostaining of ssDNA and Ki-67, respectively. Three-week cerulein injection induced pancreatic fibrosis and pancreatic atrophy with proliferation of activated PSCs. In AdTb-ExR-injected mice, but not AdLacZ-injected mice, pancreatic fibrosis was significantly attenuated. This finding was accompanied by a reduction of activated PSCs. AdTb-ExR, but not AdLacZ, significantly increased pancreas weight after chronic pancreatic injury. AdTb-ExR did not change the proportion of proliferating acinar cells, whereas it reduced the number of apoptotic acinar cells. Our results demonstrate that inhibition of TGF-b action not only decreases pancreatic fibrosis but also protects the pancreas against chronic injury by preventing acinar cell apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Replication-defective Recombinant Adenovirusesmentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibition of transforming growth factor β decreases pancreatic fibrosis and protects the pancreas against chronic injury in mice

Nagashio

Ueno

Imamura

et al. 2004

Laboratory Investigation

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“…Thus, suppression of TGF-␤ signaling has been included in several therapeutic approaches for preventing renal fibrosis. 10,11 PAI-1 is the main physiologic inhibitor of the tissue and urokinase plasminogen activator and is considered to be the most important inhibitor of fibrinolysis. 12 However, plasminogen inhibition does not explain the action of PAI-1 in renal fibrosis.…”

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confidence: 99%

The Orphan Nuclear Receptor SHP Attenuates Renal Fibrosis

Jung¹,

Kim²,

Choe

et al. 2009

Journal of the American Society of Nephrology

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The accumulation of extracellular matrix proteins is a common feature of fibrotic kidney diseases. Accumulating evidence suggests that TGF-␤ and plasminogen activator inhibitor type 1 (PAI-1) promote the development of renal fibrosis by stimulating the generation and inhibiting the removal of matrix proteins. The small heterodimer partner (SHP) represses PAI-1 expression in the liver by inhibiting TGF-␤ signaling, but whether SHP inhibits renal fibrosis is unknown. Here, unilateral ureteral obstruction (UUO) markedly increased the expression of PAI-1, type I collagen, and fibronectin but decreased SHP gene expression. Moreover, in kidneys of SHPϪ/Ϫ mice, the expression of PAI-1, type I collagen, fibronectin and ␣-smooth muscle actin (␣-SMA) were higher compared with those in kidneys of wild-type mice. In addition, loss of SHP accelerated renal fibrosis after UUO. Adenovirus-mediated overexpression of SHP in cultured rat mesangial cells and renal tubular epithelial cells inhibited TGF-␤-stimulated expression of PAI-1, type I collagen, and fibronectin. SHP inhibited TGF-␤-and Smad3-stimulated PAI-1 promoter activities as well as TGF-␤-stimulated binding of Smad3 to its consensus response element on the PAI-1 promoter. Similarly, in vivo, adenovirus-mediated overexpression of SHP in the kidney inhibited the expression of UUO-induced PAI-1, type I collagen, fibronectin, and ␣-SMA. In summary, SHP attenuates renal fibrosis in obstructive nephropathy, making its pathway a possible therapeutic target for chronic kidney disease.

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“…These drugs have proven useful in experimental rapidly progressive GN, where they inhibited the formation of crescents [61][62][63][64][65][66][67], and in mouse strains having developed spontaneously SLE [68].…”

Section: Anti -Tnfmentioning

confidence: 99%

Glomerulonephritis, Pathogenetic Mechanisms and Therapeutic Options: An Overview

Russo

Musto²,

Testorio³

et al. 2014

J Nephrol Ther

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Introduction: Most forms of human glomerulonephritis (GN) result from immunologic mechanisms that are mediated by the actions of multiple elements of both the innate and adaptive immune systems, thereby resulting in different clinical manifestations. The treatment of immune-mediated kidney disease is based on steroids and immunosuppressive drugs that interfere with the immune processes. These groups of drugs have led to significant benefits, but severe side effects are still frequent. Monoclonal antibodies directed against molecules of inflammation or several cellular components have emerged in clinical practice. Plasmapheresis and new methods to reduce the risks associated with the procedure with standard therapies may be combined. Moreover new therapeutic options have been proposed, as the use of natural anti-inflammatory cytokines or intracellular signaling reducing inflammation.

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Blockade of TGF-β action ameliorates renal dysfunction and histologic progression in anti-GBM nephritis

Cited by 45 publications

References 32 publications

Inhibition of transforming growth factor β decreases pancreatic fibrosis and protects the pancreas against chronic injury in mice

Inhibition of transforming growth factor β decreases pancreatic fibrosis and protects the pancreas against chronic injury in mice

The Orphan Nuclear Receptor SHP Attenuates Renal Fibrosis

Glomerulonephritis, Pathogenetic Mechanisms and Therapeutic Options: An Overview

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