High glucose activates the p38 MAPK pathway in cultured human peritoneal mesothelial cells

Xu, Zhihua; Kim, Kyung Sik; Park, Hyeong Cheon; Choi, Kyu Hun; Lee, Ho Yung; Han, Dae Suk; Kang, Shin Wook

doi:10.1046/j.1523-1755.2003.00836.x

Cited by 36 publications

(32 citation statements)

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“…Diabetic milieu is known to activate the p38 MAPK pathway in various cells and organs (9,13,14,16,30,44); however, the consequences of inhibiting p38 MAPK activation under diabetic conditions have not been well explored in diabetic nephropathy. In this study, we demonstrate for the first time that fibronectin expression and apoptosis in diabetic glomeruli and p38 MAPK is a member of the MAPK family and is known as a "stress-activated kinase," along with JNK (7,24,36).…”

Section: Discussionmentioning

confidence: 99%

FR167653 inhibits fibronectin expression and apoptosis in diabetic glomeruli and in high-glucose-stimulated mesangial cells

Jung

Kwak

et al. 2008

American Journal of Physiology-Renal Physiology

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Previous in vitro studies suggest that the p38 MAPK pathway may be involved in the pathogenesis of diabetic nephropathy, but the consequences of the inhibition of the p38 MAPK pathway have not been well elucidated in diabetic (DM) glomeruli. This study was undertaken to investigate the effect of p38 MAPK inhibitor, FR167653, on fibronectin expression and apoptosis in DM glomeruli and in high-glucose-stimulated mesangial cells (MC). In vivo, 32 Sprague-Dawley rats were injected with diluent (control, N ϭ 16) or streptozotocin intraperitoneally (DM, N ϭ 16). Eight rats from each group were treated with FR167653 for 3 mo. In vitro, rat MC were exposed to medium containing 5.6 mM glucose or 30 mM glucose [high glucose (HG)] with or without 10 Ϫ6 M FR167653 for 24 h. Fibronectin mRNA and protein expression were determined by real-time PCR and Western blot, respectively. Western blot for apoptosis-related molecules, terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling assay, and Hoechst 33342 staining were performed to determine apoptosis. FR167653 ameliorated the increases in fibronectin-to-GAPDH mRNA ratio and protein expression in DM glomeruli by 89 and 79% and in HGstimulated MC by 70 and 91%, respectively (P Ͻ 0.05). Under diabetic conditions, Bcl-2 protein expression was decreased, whereas cleaved caspase-3 protein expression was increased (P Ͻ 0.05), and these changes were inhibited by FR167653 treatment. Apoptotic cells were also significantly increased in DM glomeruli and in HG-stimulated MC (P Ͻ 0.05), and FR167653 ameliorated these increases in apoptotic cells, both in vivo and in vitro. In conclusion, these findings suggest that the inhibition of the p38 MAPK pathway has a beneficial effect on the development of diabetic nephropathy by inhibiting the increase in fibronectin expression and apoptosis. p38 mitogen-activated protein kinase; fibrosis; apoptosis; diabetic nephropathy THE MOLECULAR AND CELLULAR mechanisms responsible for diabetic nephropathy remain incompletely resolved. While studies indicate involvement of hyperglycemia via the stimulation of growth factor-induced cellular hypertrophy (48), increased production of extracellular matrix (ECM) protein (2), and decreased production of matrix-degrading proteinases (20), the underlying signal transduction mechanisms mediating these processes have been less well explored.Numerous studies reveal protein kinase C (PKC) activation in diabetic glomeruli (5) and in mesangial cells cultured under high-glucose conditions (42). PKC propagates the physiological responses of receptor-ligand interactions via an array of downstream signals, such as mitogen-activated protein kinases (MAPKs). p38 MAPK, a member of the MAPK family, is known to be activated in response to stress signals, such as proinflammatory cytokines (28, 34), ultraviolet irradiation (34), osmolality changes (28, 34), and oxidative stress (4, 28), leading to apoptosis (43), prostanoid production (22), and other cellular dysfunctions (8). Since hyperosmolality and oxidant stress c...

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Section: Discussionmentioning

confidence: 99%

FR167653 inhibits fibronectin expression and apoptosis in diabetic glomeruli and in high-glucose-stimulated mesangial cells

Jung

Kwak

et al. 2008

American Journal of Physiology-Renal Physiology

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“…By contrast, p38 has been implicated in sphingosine-1-phosphate-stimulated chemotaxis of rat VSMC. 15 Glucose activates the ERK1/2 pathway in VSMC 16,17 and the p38 pathway in mesothelial cells, 18 Schwann cells, 19 and endothelial cells. 17 In addition, glucopenia is also associated with activation of ERK1/2 and JNK.…”

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confidence: 99%

Glucose-Potentiated Chemotaxis in Human Vascular Smooth Muscle Is Dependent on Cross-Talk Between the PI3K and MAPK Signaling Pathways

Campbell

Allen²,

Sawyer³

et al. 2004

Circulation Research

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Abstract-Atheroma formation involves the movement of vascular smooth muscle cells (VSMC) into the subendothelial space. The aim of this study was to determine the involvement of PI3K and MAPK pathways and the importance of cross-talk between these pathways, in glucose-potentiated VSMC chemotaxis to serum factors. VSMC chemotaxis occurred in a serum gradient in 25 mmol/L glucose (but not in 5 mmol/L glucose) in association with increased phosphorylation (activation) of Akt and ERK1/2 in PI3K and MAPK pathways, respectively. Inhibitors of these pathways blocked chemotaxis, as did an mTOR inhibitor. VSMC expressed all class IA PI3K isoforms, but microinjection experiments demonstrated that only the p110␤ isoform was involved in chemotaxis. ERK1/2 phosphorylation was reduced not only by MAPK pathway inhibitors but also by PI3K and mTOR inhibitors; when PI3K was inhibited, ERK phosphorylation could be induced by microinjected activated Akt, indicating important cross-talk between the PI3K and ERK1/2 pathways. Glucose-potentiated phosphorylation of molecules in the p38 and JNK MAPK pathways inhibited these pathways but did not affect chemotaxis. The statin, mevinolin, blocked chemotaxis through its effects on the MAPK pathway. Mevinolin-inhibited chemotaxis was restored by farnesylpyrophosphate but not by geranylgeranylpyrophosphate; in the absence of mevinolin, inhibition of farnesyltransferase reduced ERK phosphorylation and blocked chemotaxis, indicating a role for the Ras family of GTPases (MAPK pathway) under these conditions. In conclusion, glucose sensitizes VSMC to serum, inducing chemotaxis via pathways involving p110␤-PI3K, Akt, mTOR, and ERK1/2 MAPK. Cross-talk between the PI3K and MAPK pathways is necessary for VSMC chemotaxis under these conditions. (Circ Res. 2004;95:380-388.)Key Words: diabetes Ⅲ atherosclerosis Ⅲ Akt Ⅲ ERK Ⅲ statin C ardiovascular disease is responsible for most of the complications associated with diabetes. Impairment of endothelium and muscle contributes to abnormalities of vasodilation. 1 Expansion of the subendothelial space occurs with the development of atheromatous plaques, which contain cellular components that have migrated from the endothelium and the tunica media, in addition to invading inflammatory cells and macrophages. 2 Both PI3K and MAPK have been implicated in chemotaxis.PI3K enzymes regulate many cellular responses, including proliferation, protection from apoptosis, intracellular vesicular transport, cytoskeletal rearrangements, and cell migration. 3 PI3Ks signal via the production of 3-phosphoinositides, lipid second messengers that bind to lipid-binding domains in a wide variety of proteins, including protein kinases (such as Akt/PKB) and regulators of small GTPases. The plectrin homology lipid-binding domain of Akt binds to the lipid products of PI3K; Akt is then recruited to the plasma membrane and phosphorylated at T308 and S473 to yield a fully activated kinase. 4 PI3Ks are heterodimers consisting of a 110-kDa catalytic subunit (p110␣, p110␤, or p110␦) in comp...

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“…We also measured the activity of MKP-1, which mediated the inactivation of p38 MAPK signaling through dephosphorylation [10]. The activations of MKP-1 protein and mRNA showed similar trends as CREB ( Fig.…”

Section: Early But Not Late Insulin Treatment Declined the Levels Of mentioning

confidence: 87%

“…We further examined the activation of CREB, an immediate downstream of p38 MAPK [10]. Similar 3 PASM staining sections of the kidneys, the glomerular volume and mesangial matrix index.…”

Section: Early But Not Late Insulin Treatment Decreased the Activatiomentioning

confidence: 99%

Early intensive insulin therapy attenuates the p38 pathway in the renal cortex and indices of nephropathy in diabetic rats

et al. 2012

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High glucose activates the p38 MAPK pathway in cultured human peritoneal mesothelial cells

Abstract: p38 MAPK activity was increased in HPMCs exposed to high glucose, in parallel with increased MKK3/6 activity and decreased MKP-1 expression, resulting in CREB activation. This activated p38 MAPK pathway may play a role in the pathogenesis of peritoneal fibrosis.

Cited by 36 publications

References 53 publications

FR167653 inhibits fibronectin expression and apoptosis in diabetic glomeruli and in high-glucose-stimulated mesangial cells

FR167653 inhibits fibronectin expression and apoptosis in diabetic glomeruli and in high-glucose-stimulated mesangial cells

Glucose-Potentiated Chemotaxis in Human Vascular Smooth Muscle Is Dependent on Cross-Talk Between the PI3K and MAPK Signaling Pathways

Early intensive insulin therapy attenuates the p38 pathway in the renal cortex and indices of nephropathy in diabetic rats

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