Angiotensin II promotes the proliferation of activated pancreatic stellate cells by Smad7 induction through a protein kinase C pathway

Hama, Kouji; Ohnishi, Hirohide; Aoki, Hiroyoshi; Kita, Hiroto; Yamamoto, Hironori; Osawa, Hiroyuki; Sato, Katsuaki; Tamada, Kiichi; Mashima, Hirosato; Yasuda, Hiroshi; Sugano, Kentaro

doi:10.1016/j.bbrc.2005.12.069

Cited by 39 publications

(33 citation statements)

References 34 publications

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“…Multiple studies have identified several major signaling pathways involved in the regulation of PaSC function (27,43,47,(50)(51)(52). MAPKs are key mediators of activating signals initiated by growth factors, angiotensin II, and ethanol (51,52).…”

Section: Mediators Of Pasc Activationmentioning

confidence: 99%

The pancreatic stellate cell: a star on the rise in pancreatic diseases

Omary¹,

Lugea²,

Lowe³

et al. 2007

J. Clin. Invest.

607

614

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Section: Mediators Of Pasc Activationmentioning

confidence: 99%

The pancreatic stellate cell: a star on the rise in pancreatic diseases

Omary¹,

Lugea²,

Lowe³

et al. 2007

J. Clin. Invest.

607

614

View full text Add to dashboard Cite

“…These central signal transduction pathways mediate activation of PSC and pancreatic fibrogenesis (5,16,25,26). We analyzed whether CCK can activate Akt, ERK, and Src signal transduction pathways in rat PSC.…”

Section: Effect Of Cck and Gastrin On Central Pro-fibrogenic Signal Tmentioning

confidence: 99%

“…These fibroblast-like cells represent only a minority of cells in the normal pancreas. Growth factors, G-protein-coupled receptors, and toxins activate PSC, leading to proliferation, migration, and production of extracellular matrix constituents including collagen, thereby inducing the organ changes characteristic of chronic pancreatitis (3)(4)(5)(6)(7)(8). These cellular effects are mediated by central signal transduction cascades including Akt, ERK, and Src.…”

mentioning

confidence: 99%

CCK1 and CCK2 Receptors Are Expressed on Pancreatic Stellate Cells and Induce Collagen Production

Berna¹,

Seiz²,

Nast

et al. 2010

Journal of Biological Chemistry

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The gastrointestinal hormone cholecystokinin (CCK) can induce acute pancreatitis in rodents through its action on acinar cells. Treatment with CCK, in combination with other agents, represents the most commonly used model to induce experimental chronic pancreatitis. Pancreatic stellate cells (PSC) are responsible for pancreatic fibrosis and therefore play a predominant role in the genesis of chronic pancreatitis. However, it is not known whether PSC express CCK receptors. Using real time PCR techniques, we demonstrate that CCK1 and CCK2 receptors are expressed on rat PSC. Interestingly both CCK and gastrin significantly induced type I collagen synthesis. Moreover, both inhibit proliferation. These effects are comparable with TGF-␤-stimulated PSC. Furthermore, the natural agonists CCK and gastrin induce activation of pro-fibrogenic pathways Akt, ERK, and Src. Using specific CCK1 and CCK2 receptor (CCK2R) inhibitors, we found that Akt activation is mainly mediated by CCK2R. Akt activation by CCK and gastrin could be inhibited by the PI3K inhibitor wortmannin. Activation of ERK and the downstream target Elk-1 could be inhibited by the MEK inhibitor U0126. These data suggest that CCK and gastrin have direct activating effects on PSC, are able to induce collagen synthesis in these cells, and therefore appear to be important regulators of pancreatic fibrogenesis. Furthermore, similar to TGF-␤, both CCK and gastrin inhibit proliferation in PSC.

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“…Angiotensin II enhanced PSCs proliferation by blocking autocrine TGF-b1-mediated growth inhibition by inducing Smad7 expression [73]. It has been proposed that an autocrine loop exists between TGF-b1 and IL-1b through Smad3-and ERK-dependent pathways [74].…”

Section: Janus-activated Kinases (Jak)/signal Transducers and Activatmentioning

confidence: 99%