Endothelin signalling and regulation of protein kinases in glomerular mesangial cells

2002 ◽  
Vol 103 (s2002) ◽  
pp. 132S-136S ◽  
Author(s):  
Andrey SOROKIN ◽  
Marco FOSCHI ◽  
Michael J. DUNN
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
Molecular Mechanisms ◽  
Mesangial Cells ◽  
Mapk Pathway ◽  
P38 Map Kinase ◽  
Dominant Negative ◽  
Glomerular Mesangial Cells ◽  
Calcium Dependent ◽  
Mitogen Activated Protein

The molecular mechanisms of endothelin (ET)-dependent activation of extracellular signal-regulated kinase (ERK)and p38 mitogen-activated protein (MAP) kinase were studied in rat and human renal glomerular mesangial cells. ET-1 induced a rapid and transient activation of Ras in renal mesangial cells, which was dependent upon the formation of the Shc/Grb2/Sos1 signalling complex and resulted in transient ERK activation. We have observed that Pyk2, a calcium-dependent cytoplasmic tyrosine kinase, was expressed in human renal mesangial cells and was tyrosine phosphorylated after ET-1 treatment. ET-1-induced activation of p38 MAPK pathway (but not ERK pathway) was inhibited in human and in rat glomerular mesangial cells expressing dominant-negative form of Pyk2, suggesting the engagement of Pyk2 in ET-1-mediated activation of p38 MAP kinase cascade. Contractive responsiveness of renal mesangial cells was shown to depend on activation of the p38 MAP kinases. Thus, p38 MAP kinase stimulation could perhaps partially account for ET-1 contractive properties, whereas ET-1-induced cell proliferation occurs primarily via Ras-dependent activation of the ERK.

scholarly journals Endothelin stimulates mitogen-activated protein kinase activity in mesangial cells through ETA.

1994 ◽  
Vol 5 (4) ◽  
pp. 1074-1080
Author(s):  
Y Wang ◽  
J Pouysségur ◽  
M J Dunn
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
Kinase Activity ◽  
Mesangial Cells ◽  
Chinese Hamster ◽  
Lung Fibroblasts ◽  
Protein Kinase Activity ◽  
Glomerular Mesangial Cells ◽  
Kinase Activation ◽  
Mitogen Activated Protein

Accumulating evidence suggests that endothelin (ET) contributes to the pathophysiology of such disorders as acute renal failure, cyclosporine-mediated renal and vascular toxicity, and perhaps even glomerular inflammation. The postreceptor signaling pathways that mediate the actions of ET in these pathophysiologic conditions may include activation of kinase cascades. Thus, the effects of ET isopeptides on p42 and p44 mitogen-activated protein (MAP) kinase activity in rat glomerular mesangial cells were examined. ET-1 activated both p42 and p44 MAP kinases with similar dose responses and different kinetics. The threshold for kinase activation was 10(-9) M ET-1. ET-1 stimulated p42 and p44 MAP kinases with similar rapid (5 min) but different sustained activation of p42 (3 to 6 h) and p44 (1 to 2 h). Endothelin-3 (ET-3) also activated both isoforms of MAP kinase but with a threshold at 10(-7) M. Compared with ET-1, ET-3 stimulated only a rapid increase of p42 MAP kinase activity. We further investigated which ET receptors are coupled to MAP kinase activation. BQ-123, an ETA blocker, completely blocked the responsiveness of the MAP kinase to either ET-1 or ET-3. In Chinese hamster lung fibroblasts transfected with ETA or ETB cDNA, both receptors showed a rapid stimulation of MAP kinase in response to ET-1. These results suggest that ET can activate MAP kinases through both ET receptors but act exclusively through ETA in glomerular mesangial cells.

scholarly journals Oxidation-triggered c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase pathways for apoptosis in human leukaemic cells stimulated by epigallocatechin-3-gallate (EGCG): a distinct pathway from those of chemically induced and receptor-mediated apoptosis

2002 ◽  
Vol 368 (3) ◽  
pp. 705-720 ◽  
Author(s):  
Koichi SAEKI ◽  
Norihiko KOBAYASHI ◽  
Yuko INAZAWA ◽  
Hong ZHANG ◽  
Hideki NISHITOH ◽  
...  
Keyword(s):  
Cell Death ◽  
Map Kinase ◽  
Map Kinases ◽  
Specific Inhibitor ◽  
P38 Map Kinase ◽  
Dominant Negative ◽  
Chemically Induced ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis

We investigated intracellular signalling pathways for apoptosis induced by epigallocatechin-3-gallate (EGCG) as compared with those induced by a toxic chemical substance (etoposide, VP16) or the death receptor ligand [tumour necrosis factor (TNF)]. EGCG as well as VP16 and TNF induced activation of two apoptosis-regulating mitogen-activated protein (MAP) kinases, namely c-Jun N-terminal kinase (JNK) and p38 MAP kinase, in both human leukaemic U937 and OCI-AML1a cells. In U937 cells, the apoptosis and activation of caspases-3 and −9 induced by EGCG but not VP16 and TNF were inhibited with SB203580, a specific inhibitor of p38, while those induced by EGCG and VP16 but not TNF were inhibited with SB202190, a rather broad inhibitor of JNK and p38. In contrast, the EGCG-induced apoptosis in OCI-AML1a cells was resistant to SB203580 but not to SB202190. Unlike TNF, EGCG did not induce the activation of nuclear factor-κB but rather induced the primary activation of caspase-9. N-Acetyl-l-cysteine (NAC) almost completely abolished apoptosis induced by EGCG under conditions in which the apoptosis induced by VP16 or TNF was not affected. The JNK/p38 activation by EGCG was also potently inhibited by NAC, whereas those by VP16 and TNF were either not or only minimally affected by NAC. In addition, dithiothreitol also suppressed both apoptosis and JNK/p38 activation by EGCG, and EGCG-induced activation of MAP kinase kinase (MKK) 3/6, MKK4 and apoptosis-regulating kinase 1 (ASK1) was suppressed by NAC. Dominant negative ASK1, MKK6, MKK4 and JNK1 potently inhibited EGCG-induced cell death. EGCG induced an intracellular increase in reactive oxygen species and GSSG, both of which were also inhibited by NAC, and the decreased synthesis of glutathione rendered the cell susceptible to EGCG-induced apoptosis. Taken together these results strongly suggest that EGCG executed apoptotic cell death via an ASK1, MKK and JNK/p38 cascade which is triggered by NAC-sensitive intracellular oxidative events in a manner distinct from chemically induced or receptor-mediated apoptosis.

p38 MAPK/HSP25 signaling mediates cadmium-induced contraction of mesangial cells and renal glomeruli

2005 ◽  
Vol 288 (6) ◽  
pp. F1133-F1143 ◽  
Author(s):  
Sahoko Hirano ◽  
Xiankui Sun ◽  
Cheryl A. DeGuzman ◽  
Richard F. Ransom ◽  
Kenneth R. McLeish ◽  
...  
Keyword(s):  
Map Kinase ◽  
P38 Mapk ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Mesangial Cells ◽  
Smooth Muscle Contraction ◽  
Environmental Pollutant ◽  
P38 Map Kinase ◽  
Dominant Negative ◽  
Kinase Activation

The environmental pollutant cadmium affects human health, with the kidney being a primary target. In addition to proximal tubules, glomeruli and their contractile mesangial cells have also been identified as targets of cadmium nephrotoxicity. Glomerular contraction is thought to contribute to reduced glomerular filtration, a characteristic of cadmium nephrotoxicity. Because p38 MAPK/HSP25 signaling has been implicated in smooth muscle contraction, we examined its role in cadmium-induced contraction of mesangial cells. We report that exposure of mesangial cells to cadmium resulted in 1) cell contraction, 2) activation of MAP kinases, 3) increased HSP25 phosphorylation coincident with p38 MAP kinase activation, 4) sequential phosphorylation of the two phosphorylation sites of mouse HSP25 with Ser15 being phosphorylated before Ser86, 5) reduction of oligomeric size of HSP25, and 6) association of HSP25 with microfilaments. Exposure of isolated rat glomeruli to cadmium also resulted in contraction and increased HSP25 phosphorylation. The cadmium-induced responses were inhibited by the specific p38 MAP kinase inhibitor SB-203580, and cadmium-induced phosphorylation of HSP25 was inhibited by expression of a dominant-negative p38 MAP kinase mutant. These findings tentatively suggest that cadmium-induced nephrotoxicity results, in part, from glomerular contraction due to p38 MAP kinase/HSP25 signaling-dependent contraction of mesangial cells. With regard to the cellular action of HSP25, these data support a change in paradigm: in addition to its well-established cytoprotective function, HSP25 may also be involved in processes that ultimately lead to adverse effects, as is observed in the response of mesangial cells to cadmium.

ERK and p38 MAP kinase are involved in arachidonic acid release induced by H2O2 and PDGF in mesangial cells

2002 ◽  
Vol 282 (3) ◽  
pp. F485-F491 ◽  
Author(s):  
Misako Hayama ◽  
Risa Inoue ◽  
Satoshi Akiba ◽  
Takashi Sato
Keyword(s):  
Arachidonic Acid ◽  
Map Kinase ◽  
Mesangial Cells ◽  
P38 Map Kinase ◽  
Arachidonic Acid Release ◽  
Cytosolic Phospholipase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Acid Release ◽  
Map Kinase Pathways

Increased prostaglandin production is implicated in the pathogenesis of glomerular disease. With this consideration, we examined the combined effects of reactive oxygen species and platelet-derived growth factor (PDGF), which might initiate glomerular dysfunction, on arachidonic acid release and cytosolic phospholipase A2 (cPLA2) activation in rat mesangial cells. H2O2-induced release of arachidonic acid was enhanced by PDGF, which by itself had little effect on the release, and the enhancement was completely inhibited by a cPLA2 inhibitor. The phosphorylation of cPLA2, extracellular signal-regulated kinase (ERK), and p38 mitogen-activated protein (MAP) kinase was upregulated by H2O2 or PDGF alone and except for ERK was enhanced further by the two in combination. The release of arachidonic acid induced by PDGF together with H2O2 was inhibited partially by an inhibitor of ERK or p38 MAP kinase and completely when the two inhibitors were combined; the inhibitory pattern was similar to that for the phosphorylation of cPLA2. These results suggest that the ERK and p38 MAP kinase pathways are involved in the increase in cPLA2activation and arachidonic acid release induced by PDGF together with H2O2.

Stimulation of pro-α1(I) collagen by TGF-β1 in mesangial cells: role of the p38 MAPK pathway

2001 ◽  
Vol 280 (3) ◽  
pp. F495-F504 ◽  
Author(s):  
Beek Yoke Chin ◽  
Amir Mohsenin ◽  
Su Xia Li ◽  
Augustine M. K. Choi ◽  
Mary E. Choi
Keyword(s):  
P38 Mapk ◽  
Intracellular Signaling ◽  
Mesangial Cells ◽  
Mapk Pathway ◽  
Dominant Negative ◽  
Glomerular Mesangial Cells ◽  
Mapk Activation ◽  
Mapk Phosphorylation ◽  
Collagen Mrna

Transforming growth factor-β1(TGF-β1) is a potent inducer of extracellular matrix protein synthesis and a key mediator of renal fibrosis. However, the intracellular signaling mechanisms by which TGF-β1stimulates this process remain incompletely understood. In this report, we examined the role of a major stress-activated intracellular signaling cascade, belonging to the mitogen-activated protein kinase (MAPK) superfamily, in mediating TGF-β1 responses in rat glomerular mesangial cells, using dominant-negative inhibition of TGF-β1 signaling receptors. We first stably transfected rat glomerular mesangial cells with a kinase-deleted mutant TGF-β type II receptor (TβR-IIM) designed to inhibit TGF-β1 signaling in a dominant-negative fashion. Next, expression of TβR-IIM mRNA was confirmed by Northern analysis. Cell surface expression and ligand binding of TβR-IIM protein were demonstrated by affinity cross-linking with 125I-labeled-TGF-β1. TGF-β1 rapidly induced p38 MAPK phosphorylation in wild-type and empty vector (pcDNA3)-transfected control mesangial cells. Interestingly, transfection with dominant-negative TβR-IIM failed to block TGF-β1-induced p38 MAPK phosphorylation. Moreover, dominant-negative TβR-IIMfailed to block TGF-β1-stimulated pro-α1(I) collagen mRNA expression and cellular protein synthesis, whereas TGF-β1-induced extracellular signal-regulated kinase (ERK) 1/ERK2 activation and antiproliferative responses were blocked by TβR-IIM. In the presence of a specific inhibitor of p38 MAPK, SB-203580, TGF-β1 was unable to stimulate pro-α1(I) collagen mRNA expression in the control and TβR-IIM-transfected mesangial cells. Finally, we confirmed that both p38 MAPK activation and pro-α1(I) collagen stimulation were TGF-β1 effects that were abrogated by dominant-negative inhibition of TGF-β type I receptor. Thus we show first demonstration of p38 MAPK activation by TGF-β1 in mesangial cells, and, given the rapid kinetics, this TGF-β1 effect is likely a direct one. Furthermore, our findings suggest that the p38 MAPK pathway functions as a component in the signaling of pro-α1(I) collagen induction by TGF-β1 in mesangial cells.

Spontaneous activation of the NF-κB signaling pathway in isolated normal glomeruli

2006 ◽  
Vol 291 (6) ◽  
pp. F1169-F1176 ◽  
Author(s):  
Kunihiro Hayakawa ◽  
Yiman Meng ◽  
Nobuhiko Hiramatsu ◽  
Ayumi Kasai ◽  
Jian Yao ◽  
...  
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
Mesangial Cells ◽  
Ex Vivo ◽  
P38 Map Kinase ◽  
Paracrine Factors ◽  
Enhancer Element ◽  
Monocyte Chemoattractant Protein 1 ◽  
Isolated Glomeruli ◽  
Tnf Α

In this report, we describe that NF-κB is spontaneously activated in isolated, normal glomeruli. Ex vivo incubation of isolated rat glomeruli triggered expression of a NF-κB-dependent gene, monocyte chemoattractant protein-1 (MCP-1), in parallel with downregulation of IκBα and IκBβ proteins and activation of the p65 NF-κB subunit. The induction of MCP-1 was also observed in mesangial cells coincubated with isolated glomeruli or exposed to media conditioned by isolated glomeruli (GCM), which was abrogated by inhibition of NF-κB. The activation of NF-κB by glomerulus-derived factors was confirmed using reporter mesangial cells that produce secreted alkaline phosphatase (SEAP) under the control of the κB enhancer element. When the reporter cells were adoptively transferred into normal glomeruli, expression of SEAP mRNA and activity of SEAP were also upregulated in the explanted glomeruli. The molecular weight of factors responsible for activation of NF-κB was >50 kDa, and TNF-α was identified as one of glomerulus-derived activators. To examine upstream events involved, we focused on MAP kinases that are spontaneously activated in explanted glomeruli. Selective suppression of ERK or p38 MAP kinase significantly attenuated activation of NF-κB in mesangial cells triggered by coculture with isolated glomeruli. Interestingly, the suppressive effects by MAP kinase inhibitors were not observed in mesangial cells treated with GCM. These data suggested that NF-κB was spontaneously activated in explanted glomeruli via autocrine/paracrine factors including TNF-α and that the production of NF-κB activators by glomeruli was, at least in part, through MAP kinase pathways.

scholarly journals Actions of Rho family small G proteins and p21-activated protein kinases on mitogen-activated protein kinase family members.

1996 ◽  
Vol 16 (7) ◽  
pp. 3707-3713 ◽  
Author(s):  
J A Frost ◽  
S Xu ◽  
M R Hutchison ◽  
S Marcus ◽  
M H Cobb
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
G Proteins ◽  
Map Kinases ◽  
P38 Map Kinase ◽  
Dominant Negative ◽  
Erk Pathway ◽  
Mitogen Activated Protein ◽  
Rho Family ◽  
Small G Proteins

The mitogen-activated protein (MAP) kinases are a family of serine/threonine kinases that are regulated by distinct extracellular stimuli. The currently known members include extracellular signal-regulated protein kinase 1 (ERK1), ERK2, the c-Jun N-terminal kinase/stress-activated protein kinases (JNK/SAPKs), and p38 MAP kinases. We find that overexpression of the Ste20-related enzymes p21-activated kinase 1 (PAK1) and PAK2 in 293 cells is sufficient to activate JNK/SAPK and to a lesser extent p38 MAP kinase but not ERK2. Rat MAP/ERK kinase kinase 1 can stimulate the activity of each of these MAP kinases. Although neither activated Rac nor the PAKs stimulate ERK2 activity, overexpression of either dominant negative Rac2 or the N-terminal regulatory domain of PAK1 inhibits Ras-mediated activation of ERK2, suggesting a permissive role for Rac in the control of the ERK pathway. Furthermore, constitutively active Rac2, Cdc42hs, and RhoA synergize with an activated form of Raf to increase ERK2 activity. These findings reveal a previously unrecognized connection between Rho family small G proteins and the ERK pathway.

scholarly journals Differential regulation of the dual-specificity protein-tyrosine phosphatases CL100, B23, and PAC1 in mesangial cells.

1997 ◽  
Vol 8 (1) ◽  
pp. 40-50
Author(s):  
D Bokemeyer ◽  
A Sorokin ◽  
M J Dunn
Keyword(s):  
Map Kinase ◽  
Intracellular Signaling ◽  
Map Kinases ◽  
Mesangial Cells ◽  
Feedback Inhibition ◽  
Protein Tyrosine Phosphatases ◽  
P38 Map Kinase ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Dual Specificity

The extracellular-signal-regulated kinase (ERK), the best described MAP kinase cascade, is a major signaling system by which cells transduce extracellular cues into intracellular responses. ERK is activated by phosphorylation both on tyrosine and threonine residues. Therefore, a new clas of protein-tyrosine phosphatases (PTPases) that exhibit dual catalytic activity toward both regulatory sites on ERK is of special interest in the control of intracellular signaling. This study examined the expression and regulation of the dual-specificity PTPases CL100, B23, and PAC1. Findings included differential expression of these phosphatases in diverse cell lines and an expression of all three dual-specificity PTPases in human mesangial cells (HMC), thereby allowing investigation of their regulation in a single cell line. The MEK antagonist PD 098059 and selective extracellular agonists of ERK were used to demonstrate the induction of CL100, PAC1, and B23 in response to activation of the ERK cascade. In contrast, anisomycin, an agonist of the recently described MAP kinases stress-activated protein kinase (SAPK) and p38 MAP kinase, stimulated CL100 gene expression but had little effect on PAC1 and B23. This effect of anisomycin was partly inhibited in the presence of the p38 MAP kinase antagonist SB 203580. This study suggests a potential mechanism to regulate ERK activity through feedback inhibition by demonstrating the ERK cascade's induction of the dual-specificity PTPases CL100, PAC1, and B23. Moreover, this study suggests an ERK-independent induction of CL100 following stimulation of SAPK and p38 MAP kinase. This mode of induction of a phosphatase capable of inactivating ERK may play an important role in the cellular stress response.

IGF-I and insulin amplify IL-1β-induced nitric oxide and prostaglandin biosynthesis

1998 ◽  
Vol 274 (4) ◽  
pp. F673-F679 ◽  
Author(s):  
Zhonghong Guan ◽  
Shaavhree Y. Buckman ◽  
Lisa D. Baier ◽  
Aubrey R. Morrison
Keyword(s):  
Nitric Oxide ◽  
Mesangial Cells ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
No Production ◽  
Glomerular Mesangial Cells ◽  
Igf I ◽  
Mitogen Activated Protein ◽  
Transduction Mechanisms ◽  
Cox 2

The inflammatory cytokine interleukin-1β (IL-1β) induces both cyclooxygenase-2 (Cox-2) and the inducible nitric oxide synthase (iNOS) with concomitant release of PGs and nitric oxide (NO) by glomerular mesangial cells. In our current studies, we determine whether insulin and IGF-I are involved in the signal transduction mechanisms resulting in IL-1β-induced NO and PGE2biosynthesis in renal mesangial cells. We demonstrate that both insulin and IGF-I increase IL-1β-induced Cox-2 and iNOS protein expression, which in turn enhance PGE2 and NO production. Our data also indicate that both insulin and IGF-I enhance IL-1β-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation and SAPK activation. These findings implicate the possible role of the MAPK pathway in mediating the effects of insulin and IGF-I on the upregulation of cytokine-stimulated NO and PG biosynthesis. Together, our results indicate that IGF-I and insulin may function to modulate the renal inflammatory process.

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