PI3K is involved in PDGF-β receptor upregulation post-PDGF-BB treatment in mouse HSC

Lechuga, Carmen G.; Hernández‐Nazará, Zamira H.; Hernández, Elizabeth; Bustamante, Marcia; Desierto, Gregory; Cotty, Adam; Dharker, Nachiket; Choe, Mu Hyeon; Rojkind, Marcos

doi:10.1152/ajpgi.00058.2005

Cited by 37 publications

(37 citation statements)

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“…100 Interestingly, although both mice with transgenic expression of either PDGF-B 103 or PDGF-C have hepatic fibrosis, 104 the PDGF-C transgenic animals also develop hepatocellular carcinoma, 104 mimicking the progression from fibrosis to cancer that occurs in human beings. Downstream consequences of PDGF signaling in stellate cells include signaling by PI3 kinase, ERK, and other pathways, [105][106][107] as well as stimulation of Na + /H + exchange, providing a potential site for therapeutic intervention by blocking ion transport. 108 Other stellate cell mitogens include VEGF, 109 thrombin and its receptor, 110,111 epidermal growth factor, TGFα, keratinocyte growth factor, 112 and basic fibroblast growth factor.…”

Section: Perpetuating Pathwaysmentioning

confidence: 99%

Mechanisms of Hepatic Fibrogenesis

2008

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Substantial improvements in the treatment of chronic liver disease have accelerated interest in uncovering the mechanisms underlying hepatic fibrosis and its resolution. Activation of resident hepatic stellate cells into proliferative, contractile, and fibrogenic cells in liver injury remains a dominant theme driving the field. However, several new areas of rapid progress in the past 5-10 years also have taken root, including: (1) identification of different fibrogenic populations apart from resident stellate cells, for example, portal fibroblasts, fibrocytes, and bone-marrow-derived cells, as well as cells derived from epithelial mesenchymal transition; (2) emergence of stellate cells as finely regulated determinants of hepatic inflammation and immunity; (3) elucidation of multiple pathways controlling gene expression during stellate cell activation including transcriptional, posttranscriptional, and epigenetic mechanisms; (4) recognition of disease-specific pathways of fibrogenesis; (5) re-emergence of hepatic macrophages as determinants of matrix degradation in fibrosis resolution and the importance of matrix cross-linking and scar maturation in determining reversibility; and (6) hints that hepatic stellate cells may contribute to hepatic stem cell behavior, cancer, and regeneration. Clinical and translational implications of these advances have become clear, and have begun to impact significantly on the management and outlook of patients with chronic liver disease.The field of hepatic fibrosis is flourishing thanks to continued experimental advances complemented by exciting progress in the treatment of chronic liver disease. 1 Control of chronic hepatitis B and C by antiviral therapies has established that advanced fibrosis can regress in association with improved clinical outcomes, 2-4 thereby intensifying enthusiasm to uncover the mechanistic basis for hepatic fibrogenesis and its attenuation. At the same time, simple paradigms defining the cellular sources of extracellular matrix (ECM), and the roles of cytokines and paracrine interactions among resident liver cells and inflammatory cells have yielded a more nuanced understanding of how the liver responds to injury. These advances have had a collateral benefit towards understanding fibrosis in other organs, particularly the pancreas. 5 Thus, a review of the mechanisms underlying hepatic fibrosis is not only timely, but is more clinically relevant than ever. This article focuses on recent advances in the field, building on established principles from earlier reviews 6,7 while weaving in their clinical relevance, but also emphasizing the molecular subtleties that have emerged through continued progress in the field. General PrinciplesFibrosis, or scarring of the liver, is a wound-healing response that engages a range of cell types and mediators to encapsulate injury. Although even acute injury will activate mechanisms of fibrogenesis, the sustained signals associated with chronic liver disease caused by infection, Cirrhosis, the most advanced stage ...

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Section: Perpetuating Pathwaysmentioning

confidence: 99%

Mechanisms of Hepatic Fibrogenesis

2008

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“…PDGFBB promotes proliferative and migratory responses of aHSC [21]. To investigate a function for UCHL1 in HSC proliferation, day 10 activated rat HSC were pre-treated with either transfection reagent alone, scrambled control siRNA or UCHL1 specific siRNAs and subsequently cultured for 24 h ± 20 ng/ml PDGFBB as a proliferative stimulus.…”

Section: Proliferation Is Significantly Reduced In Uchl1 -/-And Sirnamentioning

confidence: 99%

Ubiquitin C-terminal hydrolase 1: A novel functional marker for liver myofibroblasts and a therapeutic target in chronic liver disease

Wilson

Murphy

Leslie

et al. 2015

Journal of Hepatology

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Background & Aims-Ubiquitination is a reversible protein modification involved in the major cellular processes that define cell phenotype and behaviour. Ubiquitin modifications are removed by a large family of proteases named deubiquitinases. The role of deubiquitinases in hepatic stellate cell (HSC) activation and their contribution to fibrogenesis are poorly defined. We have identified that the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) is highly induced following HSC activation, determined its function in activated HSC and its potential as a therapeutic target for fibrosis.

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“…[1][2][3][4] PDGF appears to trigger liver regeneration after partial hepatectomy and chemical-induced acute liver cell necrosis in vivo. 6,7) The response of adult rat hepatocytes to PDGF has also been investigated extensively with respect to DNA synthesis and proliferation in vitro.…”

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Activation of Extracellular-Signal Regulated Kinase by Platelet-Derived Growth Factor Is Potentiated by Phenylephrine in Primary Cultures of Adult Rat Hepatocytes

Moteki

Kimura

Ogihara

2011

Biological & Pharmaceutical Bulletin

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Platelet-derived growth factor (PDGF) is a potent stimulator of the proliferation by connective tissue cells, such as fibroblasts, smooth muscle cells and hepatic stellate cells, [1][2][3][4] and may play a role in liver regeneration.5) PDGF-BB is reported to induce smooth muscle cells proliferation and cell migration more effectively than PDGF-AA or -AB. [1][2][3][4] PDGF appears to trigger liver regeneration after partial hepatectomy and chemical-induced acute liver cell necrosis in vivo. 6,7) The response of adult rat hepatocytes to PDGF has also been investigated extensively with respect to DNA synthesis and proliferation in vitro. 8,9) The receptor for PDGF, similarly to the receptors for epidermal growth factor (EGF), insulin and hepatocyte growth factor (HGF), contains intrinsic tyrosine kinase activity. The mitogenic effects of PDGF are reportedly mediated through the activation of tyrosine kinase-linked receptors.10) However, little is known about which of the signals originating in the plasma membrane are involved in the induction of hepatocyte DNA synthesis and proliferation by PDGF. We recently reported that PDGF is able to rapidly stimulate hepatocyte DNA synthesis and proliferation during short-term culture.11) In addition, the hepatocyte DNA synthesis and proliferation produced by PDGF was not inhibited depending on initial plating density. Furthermore, we found that hepatocyte DNA synthesis and proliferation by PDGF were potentiated by both a 1 -adrenergic agonists, but not b 2 -adrenergic agonists. 11)More recently, the signal transduction pathways activated in response to PDGF in hepatocytes and other cell types have become more clearly understood. 4,12,13) Using specific inhibitors of signal transducers, we pharmacologically demonstrated that receptor tyrosine kinase, phosphoinositide 3-kinase (PI3K), phospholipase C (PLC) and ribosomal p70 S6 kinase (p70S6K) activities are essential for PDGF-induced DNA synthesis and proliferation in primary cultures of adult rat hepatocytes. 11)In addition, extracellular-signal regulated kinase (ERK)1/2, which is the same as mitogen-activated protein kinase (p42 and p44 MAPK), is now known to be activated in response to a large number of mitogenic stimuli, and the enzyme is a key participant in the response to various growth factors and cytokines. 12,14,15) To better understand the PDGFmediated signaling pathway, we investigated whether activation of ERK isoforms, ERK1 and ERK2, is involved in PDGF-induced DNA synthesis and proliferation in primary cultures of adult rat hepatocytes.On the other hand, catecholamines (e.g., norepinephrine and its analogs) have been shown to be involved in the regulation of liver function (e.g., lipid metabolism, carbohydrate metabolism and cell growth). There are several types of catecholamine receptor; b 1 -and b 2 -adrenergic receptors stimulate adenylate cyclase, while a 2 -adrenergic receptors inhibit its activity.16) a 1 -Adrenergic receptors are related to phospholipase C (PLC) activation and subsequent increases in inos...

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PI3K is involved in PDGF-β receptor upregulation post-PDGF-BB treatment in mouse HSC

Cited by 37 publications

References 36 publications

Mechanisms of Hepatic Fibrogenesis

Mechanisms of Hepatic Fibrogenesis

Ubiquitin C-terminal hydrolase 1: A novel functional marker for liver myofibroblasts and a therapeutic target in chronic liver disease

Activation of Extracellular-Signal Regulated Kinase by Platelet-Derived Growth Factor Is Potentiated by Phenylephrine in Primary Cultures of Adult Rat Hepatocytes

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