Angiotensin II stimulates DNA synthesis of rat pancreatic stellate cells by activating ERK through EGF receptor transactivation

Hama, Kouji; Ohnishi, Hirohide; Yasuda, Hiroshi; Ueda, Norihiro; Mashima, Hirosato; Satoh, Yasuyuki; Hanatsuka, Kazunobu; Kita, Hiroto; Ohashi, Akiyoshi; Tamada, Kiichi; Sugano, Kentaro

doi:10.1016/j.bbrc.2004.01.155

Cited by 48 publications

(36 citation statements)

References 35 publications

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“…AT-II directly induces proliferation of pancreatic stellate cells as well as digestive enzyme secretion by acinar cells in vitro, both of which were abolished in the presence of ARBs (Reinehr et al, 2004;Hama et al, 2004;Tsang et al, 2004). We speculate that inhibition of AT-II by the combination therapy may have similar effects in the present model.…”

Section: Tablementioning

confidence: 50%

Combination Therapy with an Angiotensin-Converting Enzyme Inhibitor and an Angiotensin II Receptor Blocker Synergistically Suppresses Chronic Pancreatitis in Rats

Yamada

Kuno²,

Ogawa³

et al. 2004

J Pharmacol Exp Ther

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We recently demonstrated that both lisinopril and candesartan, an angiotensin-converting enzyme inhibitor and angiotensin II type 1 receptor blocker, respectively, attenuate pancreatic inflammation and fibrosis in male Wistar Bonn/Kobori (WBN/Kob) rats. The purpose of the present study was to assess whether combination therapy with low doses of both, ineffective when given alone, might synergistically exert protective effects. Lisinopril, candesartan, or a combination of both in drinking water was administered to 10-week-old male WBN/Kob rats for 10 weeks. Parameters of inflammation and fibrosis, positive immunostaining for ␣-smooth muscle actin, and gene expression of cytokine and growth factors were assessed, as well as circulating renin-angiotensin system components. Dose-dependent effects of combination therapy were also investigated. Only combination therapy attenuated gross alterations in the pancreas, as quantitatively confirmed by increases in pancreatic weights and decreases in myeloperoxidase activity, hydroxyproline content, histologic scores, relative fibrosis area, and relative area of ␣-smooth muscle actin-positive cells. Combination therapy suppressed up-regulation of tumor necrosis factor-␣, platelet-derived growth factor-receptor ␤, and transforming growth factor-␤1 mRNA in the pancreas. Dose dependence of combination therapy was recognized with reference to improvement in these parameters. The conclusions are that combination therapy synergistically alleviated pancreatic inflammation and fibrosis in male WBN/Kob rats. This effect may be related to suppression of tumor necrosis factor-␣, plateletderived growth factor-receptor ␤, and transforming growth factor-␤1 mRNA. Compared with the either therapy alone, combination therapy with an angiotensin-converting enzyme inhibitor and an angiotensin II type 1 receptor blocker may be more beneficial for treating chronic pancreatitis.

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Section: Tablementioning

confidence: 50%

Combination Therapy with an Angiotensin-Converting Enzyme Inhibitor and an Angiotensin II Receptor Blocker Synergistically Suppresses Chronic Pancreatitis in Rats

Yamada

Kuno²,

Ogawa³

et al. 2004

J Pharmacol Exp Ther

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“…There is little involvement of the AT II-AT I receptor pathway in acute pancreatic injury, but that pathway plays a crucial role in the development of pancreatic fi brosis through AT II-mediated PSC activation and proliferation. 72 In an in vitro study, Hama et al 73 demonstrated that AT II stimulates PSC proliferation by transactivating the epidermal growth factor (EGF)-receptor, which leads to ERK activation, and that an EGF-receptor kinase inhibitor reduced AT IIstimulated DNA synthesis by PSCs. They subsequently demonstrated that AT II inhibits TGF-β-induced nuclear accumulation of Smad3 and Smad4, and rapidly induces expression of inhibitory Smad7.…”

Section: Inhibitors Of the Renin-angiotensin Systemmentioning

confidence: 98%

Mechanisms of pancreatic fibrosis and applications to the treatment of chronic pancreatitis

Shimizu

2008

J Gastroenterol

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Pancreatic stellate cells (PSCs) play a crucial role in pancreatic fibrogenesis in chronic pancreatitis and in the desmoplastic reaction of pancreatic cancer. When PSCs are stimulated by oxidative stress, ethanol and its metabolite acetaldehyde, and cytokines, the phenotype of quiescent fat-storing cells converts to myofibroblastlike activated PSCs, which then produce extracellular matrix, adhesion molecules, and various chemokines in response to cytokines and growth factors. Recent data suggest that PSCs have a phagocytic function. Plateletderived growth factor is a potent stimulator of PSC proliferation. Transforming growth factor beta, activin A, and connective tissue growth factor also play a role in PSC-mediated pancreatic fibrogenesis through autocrine and paracrine loops. Following pancreatic damage, pathophysiological processes that occur in the pancreas, including pancreas tissue pressure, hyperglycemia, intracellular reactive oxygen species production, activation of protease-activated receptor 2, induction of cyclooxygenase 2, and bacterial infection play a role in sustaining pancreatic fibrosis through increased PSC proliferation and collagen production by PSCs. Targeting PSCs might be an effective therapeutic approach in chronic pancreatitis. Various substances including vitamin A, vitamin E, polyphenols, peroxisome proliferator-activated receptor gamma ligands, and inhibitors of the renin-angiotensin system show great promise of being useful in the treatment of chronic pancreatitis.

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“…Furthermore, it has been reported that the AngII signal is induced by activation of epidermal growth factor receptor, by ERK activation, and by PKC-dependent Smad7. 35 Other reports suggest that proliferation of PSCs is induced by a factor contained in the supernatant of pancreatic cancer cells and that this proliferation also involves ERK. 39,40 Whereas various pathways for proliferation have been reported, most of them involve activation of ERK, and very few reports mentioned other pathways.…”

Section: Discussionmentioning

confidence: 98%

Bacterial DNA Promotes Proliferation of Rat Pancreatic Stellate Cells Thorough Toll-Like Receptor 9

Nakamura¹,

Ito²,

Oono³

et al. 2011

Pancreas

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Angiotensin II stimulates DNA synthesis of rat pancreatic stellate cells by activating ERK through EGF receptor transactivation

Cited by 48 publications

References 35 publications

Combination Therapy with an Angiotensin-Converting Enzyme Inhibitor and an Angiotensin II Receptor Blocker Synergistically Suppresses Chronic Pancreatitis in Rats

Combination Therapy with an Angiotensin-Converting Enzyme Inhibitor and an Angiotensin II Receptor Blocker Synergistically Suppresses Chronic Pancreatitis in Rats

Mechanisms of pancreatic fibrosis and applications to the treatment of chronic pancreatitis

Bacterial DNA Promotes Proliferation of Rat Pancreatic Stellate Cells Thorough Toll-Like Receptor 9

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