High Glucose Activates Rat Pancreatic Stellate Cells Through Protein Kinase C and p38 Mitogen-Activated Protein Kinase Pathway

Nomiyama, Yoko; Tashiro, Mitsuo; Yamaguchi, Taizo; Watanabe, Shiro; Taguchi, Masashi; Asaumi, Hiroshi; Nakamura, Hayato; Ōtsuki, Makoto

doi:10.1097/mpa.0b013e31802f0531

Cited by 56 publications

(34 citation statements)

References 42 publications

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“…Previous studies have shown that PMA can induce p38 activation (Chang et al, 2005; Kitatani et al, 2006; Nomura et al, 2007) and implicated PKC upstream of p38 MAPK (Woo et al, 2005; Nomiyama et al, 2007). Given that PKC- δ and nSMase2 did not seem to interact, it became important to determine the role of PKC with respect to p38 MAPK in regulating nSMase2 translocation.…”

Section: Resultsmentioning

confidence: 99%

“…For example, PKC- δ has been implicated in regulation of apoptosis of U937 cells (Jang et al, 2003), whereas PKC-ε is involved in UV-induced carcinoma development (Aziz et al, 2007). A role for PKCs in p38 MAPK activation has also been suggested in response to TNF and hyperglycemia (Woo et al, 2005; Nomiyama et al, 2007), and PMA induces p38 MAPK activation in many cell types, including MCF-7, A549, and A172 glioblastoma cells (Chang et al, 2005; Kitatani et al, 2006; Nomura et al, 2007). Thus, some of the downstream effects of PKC can be attributed to its subsequent activation of p38 MAPK.…”

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confidence: 98%

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Regulation of Neutral Sphingomyelinase-2 (nSMase2) by Tumor Necrosis Factor-α Involves Protein Kinase C-δ in Lung Epithelial Cells

Clarke¹,

Guthrie²,

Hannun³

2008

Mol Pharmacol

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Neutral sphingomyelinases (N-SMases) are major candidates for stress-induced ceramide production, but there is still limited knowledge of the regulatory mechanisms of the cloned N-SMase enzyme—nSMase2. We have reported that p38 mitogen-activated protein kinase (MAPK) was upstream of nSMase2 in tumor necrosis-α (TNF-α)-stimulated A549 cells (J Biol Chem 282:1384–1396, 2007). Here, we report a role for protein kinase C (PKC) in mediating TNF-induced translocation of nSMase2 from the Golgi to the plasma membrane (PM). Pharmacological inhibition of PKCs prevented TNF-stimulated nSMase2 translocation to the PM in A549 cells. Using phorbol 12-myristate 13-acetate (PMA) as a tool to dissect PKC responses, we found that PMA induced nSMase2 translocation to the PM in a time- and dose-dependent manner. Pharmacological inhibitors and specific siRNA implicated the novel PKCs, specifically PKC-δ, in both TNF and PMA-stimulated nSMase2 translocation. However, PMA did not increase in vitro N-SMase activity and PKC-δ did not regulate TNF-induced N-SMase activity. Furthermore, PKC-δ and nSMase2 did not coimmunoprecipitate, suggesting that other signaling proteins may be involved. PMA-stimulated nSMase2 translocation was independent of p38 MAPK, and neither PKC inhibitors nor small interfering RNA had significant effects on TNF-stimulated p38 MAPK activation, indicating that PKC-δ does not act through p38 MAPK in regulating nSMase2. Finally, down-regulation of PKC-δ inhibited induction of vascular cell and intercellular adhesion molecules, previously identified as downstream of nSMase2 in A549 cells. Taken together, these data implicate PKC-δ as a regulator of nSMase2 and, for the first time, identify nSMase2 as a point of cross-talk between the PKC and sphingolipid pathways.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 98%

Regulation of Neutral Sphingomyelinase-2 (nSMase2) by Tumor Necrosis Factor-α Involves Protein Kinase C-δ in Lung Epithelial Cells

Clarke¹,

Guthrie²,

Hannun³

2008

Mol Pharmacol

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“…In addition, in vitro studies showed that high concentration of glucose (which can result from sucrose feeding) induced pancreatic stellate cell (PSC) proliferation, resulting in increased extracellular matrix production and a consequent aggravation of fibrosis (37,38). High glucose and high insulin have been reported to have an additive effect on the activation and proliferation of rat PSCs (39).…”

Section: Discussionmentioning

confidence: 99%

Palatinose and oleic acid act together to prevent pancreatic islet disruption in nondiabetic obese Zucker rats

et al. 2008

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: We showed previously that 8-wk consumption of a diet containing palatinose (P, a slowly-absorbed sucrose analogue) and oleic acid (O) ameliorates but a diet containing sucrose (S) and linoleic acid (L) aggravates metabolic abnormalities in Zucker fatty (fa/fa) rats. In this study, we aimed to identify early changes in metabolism in rats induced by certain combinations of carbohydrates and fatty acids. Specifically, male Zucker fatty rats were fed an isocaloric diet containing various combinations of carbohydrates (P ; S) and fatty acids (O ; L). After 4 wk, no significant differences in body weight, visceral fat mass, plasma parameters (glucose, insulin, lipids, and adipokines), hepatic adiposity and gene expression, and adipose inflammation were observed between dietary groups. In contrast, pancreatic islets of palatinose-fed (PO and PL) rats were smaller and less fibrotic than sucrose-fed (SO and SL) rats. The abnormal ! -cell distribution and sporadic staining of active caspase-3 common to islets of linoleic-acid-fed rats were not observed in oleic-acid-fed (PO and SO) rats. Accordingly, progressive " -cell loss was seen in SL rats, but not in PO rats. These findings suggest that pancreatic islets may be initial sites that translate the effects of different combinations of dietary carbohydrates and fats into metabolic changes.

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“…It was demonstrated that hyperglycemia promotes proliferation and activation of PSCs and stimulates collagen production of PSCs via protein kina-seC-p38 mitogen-activated protein kinase pathway, resulting in pancreatic fibrosis [59] .…”

Section: Clinical Studiesmentioning

confidence: 99%

Interactions between the Endocrine and Exocrine Pancreas and Their Clinical Relevance

et al. 2009

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High Glucose Activates Rat Pancreatic Stellate Cells Through Protein Kinase C and p38 Mitogen-Activated Protein Kinase Pathway

Abstract: Our results indicate that high glucose concentrations stimulate PSC activation via PKC-p38 MAP kinase pathway and suggest that high glucose may aggravate pancreatic fibrosis.

Cited by 56 publications

References 42 publications

Regulation of Neutral Sphingomyelinase-2 (nSMase2) by Tumor Necrosis Factor-α Involves Protein Kinase C-δ in Lung Epithelial Cells

Regulation of Neutral Sphingomyelinase-2 (nSMase2) by Tumor Necrosis Factor-α Involves Protein Kinase C-δ in Lung Epithelial Cells

Palatinose and oleic acid act together to prevent pancreatic islet disruption in nondiabetic obese Zucker rats

Interactions between the Endocrine and Exocrine Pancreas and Their Clinical Relevance

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