High glucose-enhanced activation of mesangial cell p38 MAPK by ET-1, ANG II, and platelet-derived growth factor

2002 ◽  
Vol 282 (1) ◽  
pp. E161-E169 ◽  
Author(s):  
Evangelia Tsiani ◽  
Poli Lekas ◽  
I. George Fantus ◽  
John Dlugosz ◽  
Catharine Whiteside
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Protein Kinase ◽  
High Glucose ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Platelet Derived Growth Factor ◽  
Ang Ii ◽  
Creb Phosphorylation

Mitogen-activated protein kinase (MAPK) p38 is activated in response to stress stimuli and growth factors relevant to the pathogenesis of diabetic nephropathy. We postulated that mesangial cells exposed to high glucose and to endothelin-1 (ET-1), angiotensin II (ANG II), and platelet-derived growth factor (PDGF) demonstrate enhanced p38 activity and subsequent activation of the cAMP responsive element binding (CREB) transcription factor. Primary rat mesangial cells exposed to 5.6 (NG) or 30 mM glucose (HG) or NG plus 24.4 mM sorbitol (osmotic control) for ≤4 days were acutely stimulated with ET-1, ANG II, or PDGF. After 3 days of HG, p38 phosphorylation and kinase activity increased twofold ( P < 0.05 vs. NG, n = 5). No change in p38 activity was observed with sorbitol. In HG, activation of p38 by ET-1, ANG II, or PDGF was enhanced compared with NG and was protein kinase C (PKC) independent. In HG, CREB phosphorylation in response to ET-1, ANG II, and PDGF stimulation was enhanced compared with NG and was abolished by p38 inhibition with SB202190. To conclude, in HG, mesangial cell p38 is activated, which in turn stimulates CREB phosphorylation. Furthermore, in HG, mesangial cell p38 responsiveness to ET-1, ANG II, and PDGF and consequent CREB phosphorylation are enhanced through a PKC-independent pathway, which may contribute to the pathogenesis of diabetic nephropathy.

Stretch-induced mesangial cell ERK1/ERK2 activation is enhanced in high glucose by decreased dephosphorylation

2000 ◽  
Vol 279 (4) ◽  
pp. F688-F697 ◽  
Author(s):  
J. A. Dlugosz ◽  
S. Munk ◽  
J. Kapor-Drezgic ◽  
H. J. Goldberg ◽  
I. G. Fantus ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Protein Kinase ◽  
High Glucose ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Mechanical Stretch ◽  
Atp Depletion ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Arginine Glycine Aspartic Acid

Glomerular hypertension and hyperglycemia are major determinants of diabetic nephropathy. We sought to identify the mechanisms whereby stretch-induced activation of mesangial cell extracellular signal-regulated kinase 1 and 2 (ERK1/ERK2) is enhanced in high glucose (HG). Mesangial cells cultured on fibronectin Flex I plates in normal glucose (NG; 5.6 mM) or HG (30 mM), were stretched by 15% elongation at 60 cycles/min for up to 60 min. In HG, a 5-min stretch increased ERK1/ERK2 phosphorylation by 6.4 ± 0.4/4.3 ± 0.3-fold ( P < 0.05 vs. NG stretch). In constrast, p38 phosphorylation was increased identically by stretch in NG and HG. Unlike many effects of HG, augmentation of ERK activity by HG was not dependent on protein kinase C (PKC) as indicated by downregulation of PKC with 24-h phorbol ester or inhibition with bisindolylmaleimide IV. In both NG and HG, pretreatment with arginine-glycine-aspartic acid peptide (0.5 mg/ml) to inhibit integrin binding or with cytochalasin D (100 ng/ml) to disassemble filamentous (F) actin, significantly reduced phosphorylation of ERK1/ERK2 and p38. To determine whether the rate of mitogen-activated protein kinase dephosphorylation is affected by HG, cellular kinase activity was inhibited by depleting ATP. Post-ATP depletion, phosphorylation of ERK1/ERK2 was reduced to 36 ± 9/51 ± 14% vs. 9 ± 5/7 ± 6% in NG ( P < 0.05, n = 5). Thus stretch-induced ERK1/ERK2 and p38 activation in both NG and HG is β1-integrin and F-actin dependent. Stretch-induced ERK1/ERK2 is enhanced in high glucose by diminished dephosphorylation, suggesting reduced phosphatase activity in the diabetic milieu. Enhanced mesangial cell ERK1/ERK2 signaling in response to the combined effects of mechanical stretch and HG may contribute to the pathogenesis of diabetic nephropathy.

scholarly journals Connective tissue growth factor (CTGF) promotes activated mesangial cell survival via up-regulation of mitogen-activated protein kinase phosphatase-1 (MKP-1)

2007 ◽  
Vol 406 (1) ◽  
pp. 131-138 ◽  
Author(s):  
Nadia Wahab ◽  
Dimity Cox ◽  
Abigail Witherden ◽  
Roger M. Mason
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Protein Kinase ◽  
Connective Tissue ◽  
P38 Mapk ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Tissue Growth ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

Activated mesangial cells are thought to play a pivotal role in the development of kidney fibrosis under chronic pathological conditions, including DN (diabetic nephropathy). Their prolonged survival may enhance the development of the disease since they express increased amounts of growth factors and extracellular matrix proteins. CTGF (connective tissue growth factor) is one of the growth factors produced by activated mesangial cells and is reported to play a key role in the pathogenesis of DN. Previous studies have shown that addition of exogenous CTGF to HMCs (human mesangial cells) rapidly activates ERK1/2 (extracellular-signal-regulated kinase 1/2) MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase) MAPK, but not the p38 MAPK, despite the activation of the upstream kinases, MKK3/6 (MAPK kinase 3/6). The aim of the present study was to investigate whether the lack of phosphorylated p38 MAPK by CTGF has an anti-apoptotic effect on activated HMCs. We show that in HMC CTGF induces the rapid transcriptional activation and synthesis of MKP-1 (MAPK phosphatase-1), a dual specificity phosphatase that dephosphorylates p38 MAPK. This in turn prevents the anti-apoptotic protein, Bcl-2, from being phosphorylated and losing its function, leading to the survival of the cells. Knockout of MKP-1 protein in mesangial cells treated with CTGF, using siRNA (small interfering RNA) or antisense oligonucleotides, allows p38 MAPK activation and induces mesangial cell death.

Mesangial cell protein kinase C isozyme activation in the diabetic milieu

2002 ◽  
Vol 282 (6) ◽  
pp. F975-F980 ◽  
Author(s):  
Catharine I. Whiteside ◽  
John A. Dlugosz
Keyword(s):  
Diabetic Nephropathy ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
High Glucose ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Cell Protein ◽  
Kinase C ◽  
Pkc Β ◽  
Vasoactive Peptide

High-glucose-induced activation of mesangial cell protein kinase C (PKC) contributes significantly to the pathogenesis of diabetic nephropathy. Excess glucose metabolism through the polyol pathway leads to de novo synthesis of both diacylglyerol (DAG) and phosphatidic acid, which may account for increased mesangial cell PKC-α, -β, -δ, -ε, and -ζ activation/translocation observed within 48-h exposure to high glucose. Raised intracellular glucose causes generation of reactive oxygen species that may directly activate PKC isozymes and enhance their reactivity to vasoactive peptide signaling. In both diabetic rodent models of diabetes and cultured mesangial cells, PKC-β appears to be the key isozyme required for the enhanced expression of transforming growth factor-β1, initiation of early accumulation of mesangial matrix protein, and increased microalbuminuria. Enhanced collagen IV expression by mesangial cells in response to vasoactive peptide hormone stimulation, e.g., endothelin-1, requires PKC-β, -δ, -ε and -ζ. Loss of mesangial cell contractility to potent vasoactive peptides and coincident F-actin disassembly are due to high-glucose-activation of PKC-ζ. Inhibition of mesangial cell PKC isozyme activation in high glucose may prove to be the next important treatment for diabetic nephropathy.

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