Mitogen-Activated Protein Kinase Cascade Is Activated in Glomeruli of Diabetic Rats and Glomerular Mesangial Cells Cultured Under High Glucose Conditions

Haneda, Masakazu; Araki, Shin‐ichi; Togawa, Masaki; Sugimoto, Toshiro; Isono, Motohide; Kikkawa, Ryuichi

doi:10.2337/diab.46.5.847

Cited by 197 publications

(118 citation statements)

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“…One mechanism by which high ambient glucose could induce ERK activity is through PKC (28). When cells were conditioned to glucose in the presence of a general PKC inhibitor, calphostin C (0.1 M), the effects of glucose on ERK activity were completely inhibited ( Figure 7B).…”

Section: Mechanism Of Erk Activation In High Glucose: Role For Pkc␦mentioning

confidence: 90%

“…Stimulation of ERK has been reported in the diabetic milieu (27)(28)(29). To determine whether glucose-induced ERK activity contributes to sensitizing Smad to TGF-␤1 in high ambient glucose conditions, we conditioned cells to glucose in the presence of the mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK inhibitor PD98059 (10 M).…”

Section: Role For Erk In Smad Activitymentioning

confidence: 99%

“…Any of these events could have an impact on Smad signaling. For example, elevated ERK activity, which can enhance Smad activity (19,21), has been reported in glomeruli from diabetic rats or in mesangial cells cultured with high-glucose medium (27)(28)(29).…”

mentioning

confidence: 99%

“…One potential mechanism is through PKC activity (28). The PKC family of serine/threonine kinases consists of at least 12 isozymes that are classified into (1) conventional PKC␣, -␤ I and II , -␥ that depend on Ca 2ϩ and DAG or phorbol ester for activation; (2) novel PKC␦, -⑀, -, and -that are Ca 2ϩ independent but DAG or phorbol ester sensitive; and (3) atypical PKC , -, and -that require neither Ca 2ϩ nor phospholipids.…”

mentioning

confidence: 99%

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High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells

Hayashida¹,

Schnaper²

2004

Journal of the American Society of Nephrology

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Abstract. High ambient glucose activates intracellular signaling pathways to induce cytokines such as TGF-␤1 in the extracellular matrix accumulation of diabetic nephropathy. These same pathways also may directly modulate TGF-␤1 signaling. R-Smad phosphorylation, association with Smad4, and nuclear accumulation after TGF-␤1 treatment (1.0 ng/ml) were significantly higher in mesangial cells that were conditioned to 20 mM glucose for 72 h than mesangial cells in 6.5 mM glucose, suggesting that high glucose enhanced responsiveness to TGF-␤1. Neither TGF-␤1 bioactivity nor TGF-␤ receptor binding was significantly different between in 6.5 and 20 mM glucose-conditioned cultures. Furthermore, adding a neutralizing anti-TGF-␤1 antibody during glucose conditioning did not affect the enhanced Smad responsiveness, indicating that enhancement likely did not result from increased TGF-␤ expression. In contrast, a mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK inhibitor, PD98059, completely abrogated the effect of high glucose. Glucose stimulation of ERK was inhibited by the general protein kinase C (PKC) inhibitor calphostin C and by the PKC␦-specific inhibitor rottlerin, whereas Gö6976, an inhibitor of conventional PKC, had no effect on ERK activity. Specificity of the PKC inhibitors was further verified by PKC␤ and ␦ kinase assay. High glucose increased expression of several PKC isozymes, but only PKC␦ showed proportionally increased membrane translocation and kinase activity in cells that were conditioned to 20 mM glucose. Finally, both ERK and PKC␦ inhibition during glucose conditioning abrogated enhanced ␣1(I) collagen mRNA and promoter induction by TGF-␤1. Taken together, these data strongly suggest that heightened ERK and PKC␦ activity in high ambient glucose conditions interact with the Smad pathway, leading to enhanced responsiveness to TGF-␤1 and increased extracellular matrix production in mesangial cells.

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Section: Mechanism Of Erk Activation In High Glucose: Role For Pkc␦mentioning

confidence: 90%

Section: Role For Erk In Smad Activitymentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells

Hayashida¹,

Schnaper²

2004

Journal of the American Society of Nephrology

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“…The next important step in the development of understanding of these processes in the kidney came with the observation that calphostin C, a PKC inhibitor, prevented activation of MAP kinase and phospholipase A 2 in mesangial cells cultured in high glucose [104]. The polyol pathway was also tied into these phenomena with the observation that an aldose reductase inhibitor prevented the activation of phospholipase A 2 in glomeruli from diabetic rats [105].…”

Section: Protein Kinase Cmentioning

confidence: 99%

Mitogen-activated protein kinases as glucose transducers for diabetic complications

1999

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The results of the Diabetes Control and Complications Trial [1] emphatically confirmed the heroic studies of Jean Pirart [2±4], showing that poor control of glycaemia in Type I (insulin-dependent) diabetes mellitus predisposes patients to chronic complications. This has led to the tacit assumption that glucose, at supranormal concentrations, is the agent of damage. Participation of hypoinsulinaemia or other manifestations of poor control cannot be discounted but glucose itself certainly has the capacity to disturb biosystems. It can do this in a variety of ways, so that hypotheses to explain specific complications ± retinopathy, nephropathy and neuropathy ± starting from high glucose are tenable, testable and, therefore, useful.Figure 1 presents a simple generic plan by which complications develop. It usefully discriminates between metabolic effects of glucose on the target cells showing the complication and the exacerbating effect of independent accelerators, such as arterial hypertension in diabetic nephropathy. Not all independent accelerators have, however, as clearly defined a rela- Diabetologia (1999) AbstractThe damaging effects of glucose on the cells which contribute to the development of diabetic complications are ill-understood. There are three major hypotheses ± the sorbitol pathway, non-enzymatic glycation of proteins and increased oxidative stress ± and many examples illustrate inter-connections between the three. It is suggested that these pathways, together with other biochemical anomalies arising from hyperglycaemia, can synergise by sharing the capacity to activate mitogen-activated protein kinases (MAP kinases) and that these enzymes in actual fact form glucose transducers. The more recent hypothesis, namely that activation of a specific isoform of protein kinase C (PKC) underpin damaging changes in retinopathy and neuropathy, can also be related because protein kinase C is an effective activator of mitogen-activated protein kinases. These latter kinases phosphorylate transcription factors, which in turn alter the balance of gene expression. In this way they can alter cellular phenotype, promote division or increase production of extracellular material. In short, mitogen-activated protein kinases have the capacity to trigger all the cellular events necessary for the development of diabetic nephropathy, retinopathy and neuropathy and it is suggested that their pharmacological modulation might provide therapeutic control of these conditions. [Diabetologia (1999

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High glucose-induced inhibition of ?-methyl-D-glucopyranoside uptake is mediated by protein kinase C-dependent activation of arachidonic acid release in primary cultured rabbit renal proximal tubule cells

2000

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Abnormal glucose handling in the proximal tubule may play an important role in the development of diabetic nephropathy. Thus, the present study was designed to examine the effect of high glucose on alpha-methyl-D-glucopyranoside (alpha-MG) uptake and its signaling pathways in the primary cultured rabbit renal proximal tubule cells (PTCs). When PTCs were preincubated with 25 or 50 mM glucose for 4 h, 25 or 50 mM glucose significantly inhibited alpha-MG uptake, while 25 or 50 mM mannitol and L-glucose did not affect. Actinomycin D and cycloheximide did not block the effect of high glucose on alpha-MG uptake. Twenty-five millimoles glucose-induced inhibition of alpha-MG uptake was blocked by mepacrine and AACOCF(3), phospholipase A(2) (PLA(2)) inhibitors. Twenty-five millimoles of glucose, not mannitol or L-glucose, significantly increased the [(3)H]-arachidonic acid (AA) release compared to control. In addition, the 25 mM glucose-induced [(3)H]-AA release was completely blocked by mepacrine or AACOCF(3). Indomethacin, a cyclooxygenase inhibitor, blocked the high glucose-induced inhibition of alpha-MG uptake, although econazole, cytochrome P-450 a epoxygenase inhibitor, and nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, did not. On the other hand, staurosporine and bisindolylmaleimide I, protein kinase C (PKC) inhibitors, blocked 25 mM glucose-induced increase of [(3)H]-AA release and inhibition of alpha-MG uptake. However, neomycin, U 73122, and phospholipase c(PLC) inhibitors did not block the effect of 25 mM glucose on [(3)H]-AA release and alpha-MG uptake. Pretreatment of methoxyverapamil, an L-type Ca(2+) channel blocker, abolished 25 mM glucose-induced increase of [(3)H]-AA release. Indeed, 25 mM glucose increased translocation of cPLA(2) from cytosolic fraction to membrane fraction. In conclusion, the present results demonstrate that high glucose inhibits alpha-MG uptake by the increase of AA release via the activation of PKC.

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Mitogen-Activated Protein Kinase Cascade Is Activated in Glomeruli of Diabetic Rats and Glomerular Mesangial Cells Cultured Under High Glucose Conditions

Cited by 197 publications

References 0 publications

High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells

High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells

Mitogen-activated protein kinases as glucose transducers for diabetic complications

High glucose-induced inhibition of ?-methyl-D-glucopyranoside uptake is mediated by protein kinase C-dependent activation of arachidonic acid release in primary cultured rabbit renal proximal tubule cells

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