Stimulation by extracellular ATP and UTP of the stress‐activated protein kinase cascade in rat renal mesangial cells

Huwiler, Andrea; Rossum, Gerda van; Wartmann, Markus; Pfeilschifter, Josef

doi:10.1038/sj.bjp.0700979

Cited by 43 publications

(34 citation statements)

References 56 publications

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“…This result suggests that extracellular ATP induces rapid and transient phosphorylation of ERK1/2, consistent with previous studies [12,19,20,23] . However, in contrast to previous studies, we found that stimulation of rat mesangial cells with ATP for 60 min resulted in decreased p-ERK1/2 levels when compared with the control.…”

Section: Discussionsupporting

confidence: 81%

“…These results suggested a role for ATP in high glucose-induced ROS generation in rat mesangial cell. The concentration of ATP used here is similar to that previously reported [14,15,18] and similar to that which has been previously shown to induce proliferation and abnormal secretion of TGF-β1 and ECM in mesangial cells [17,19,20] . Studies have shown that the generation of ROS induced by ATP is associated with an increase in intracellular Ca 2+ levels [14,15,18] .…”

Section: Discussionsupporting

confidence: 67%

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Adenosine 5′-triphosphate stimulates the increase of TGF-β1 in rat mesangial cells under high-glucose conditions via reactive oxygen species and ERK1/2

Xue

Yuan

et al. 2009

Acta Pharmacol Sin

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Aim: To investigate the role of adenosine 5′-triphosphate (ATP)-induced generation of reactive oxygen species (ROS) and phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the production of transforming growth factor-β1 (TGF-β1) in cultured rat glomerular mesangial cells under high-glucose conditions. Methods: Subconfluent glomerular mesangial cells were serum-starved for 24 h and pretreated with suramin, diphenylenechloride iodonium (DPI) or PD98059 followed by stimulation with a high concentration of glucose (30 mmol/L D-glucose) or ATP (300 μmol/L). Extracellular and total ATP and ROS production were detected using commercially available kits. Phosphorylation of ERK1/2 was evaluated by Western blot. TGF-β1 mRNA expression was examined by real-time PCR. Results: Suramin had a dose-dependent inhibitory effect on the generation of ROS induced by high glucose. Extracellular ATP production by mesangial cells increased markedly after a 2-h incubation with high glucose. ROS production was upregulated in mesangial cells after 5 min incubation with 300 μmol/L ATP and was sustained for 120 min. ERK1/2 was significantly activated after 5 min incubation of mesangial cells with ATP, this activation was partially inhibited by DPI. The effects of high glucose on TGF-β1 mRNA were markedly inhibited by suramin, DPI or PD98059. Conclusion: Our results suggest that a high concentration of glucose increases the extracellular levels of ATP in mesangial cells within a short time-frame. ATP, in turn, activates ERK1/2, an effect which is at least partially dependent on ROS, which results in the upregulation of TGF-β1.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 67%

Adenosine 5′-triphosphate stimulates the increase of TGF-β1 in rat mesangial cells under high-glucose conditions via reactive oxygen species and ERK1/2

Xue

Yuan

et al. 2009

Acta Pharmacol Sin

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“…Whether changes in HuR phosphorylation, either by different PKCs or by the MAPK pathway, account for the ATP-induced HuR redistribution in MC is currently being investigated in our laboratory. In this context it is noteworthy that ATP has been shown to activate different PKC isoenzymes (14,15) as well as the three major MAPK cascades (18,30,31).…”

Section: Atp-inducible Complexes Binding To Mmp-9-specific Ares Contamentioning

confidence: 99%

“…The stimulatory effects of ATP on MMP-9 expression could be potently inhibited by the addition of suramin, a potent, although nonselective, antagonist of P2Y 2 purinoceptors. The occupation of P2Y 2 receptors in rat MC can activate different isoforms of protein kinase C (PKC) (15,24) but also different MAPK pathways including the extracellular signal-regulated kinases (18), the stress-activated protein kinase, and p38-MAPK cascade (30,31). Interestingly, several studies have implicated MAPK pathways as well as PKC-dependent signaling cascades in the up-regulation of MMP-9 expression (32-35), mainly via the activation of NF-B and AP-1 transcription factors (6,(33)(34)(35).…”

Section: Atp-inducible Complexes Binding To Mmp-9-specific Ares Contamentioning

confidence: 99%

ATP Potentiates Interleukin-1β-induced MMP-9 Expression in Mesangial Cells via Recruitment of the ELAV Protein HuR

Huwiler

Akool

Aschrafi

et al. 2003

Journal of Biological Chemistry

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Renal mesangial cells express high levels of matrix metalloproteinase 9 (MMP-9) in response to inflammatory cytokines such as interleukin (IL)-1␤. We demonstrate here that the stable ATP analog adenosine 5-O-(thiotriphosphate) (ATP␥S) potently amplifies the cytokine-induced gelatinolytic content of mesangial cells mainly by an increase in the MMP-9 steady-state mRNA level. A Luciferase reporter gene containing 1.3 kb of the MMP-9 5-promoter region showed weak responses to ATP␥S but confered a strong ATP-dependent increase in Luciferase activity when under the additional control of the 3-untranslated region of MMP-9. By in vitro degradation assay and actinomycin D experiments we found that ATP␥S potently delayed the decay of MMP-9 mRNA. Gel-shift and supershift assays demonstrated that three AU-rich elements (AREs) present in the 3-untranslated region of MMP-9 are constitutively bound by complexes containing the mRNA stabilizing factor HuR. The RNA binding of these complexes was markedly increased by ATP␥S. Mutation of each ARE element strongly impaired the RNA binding of the HuR containing complexes. Reporter gene assays revealed that mutation of one ARE did not affect the stimulatory effects by ATP␥S, but mutation of all three ARE motifs caused a loss of ATP-dependent increase in luciferase activity without affecting IL-1␤-inducibility. By confocal microscopy we demonstrate that ATP␥S increased the nucleo cytoplasmic shuttling of HuR and caused an increase in the cytosolic HuR level as shown by cell fractionation experiments. Together, our results indicate that the amplification of MMP-9 expression by extracellular ATP is triggered through mechanisms that likely involve a HuR-dependent rise in MMP-9 mRNA stability.The matrix metalloproteinases (MMPs) 1 are members of a family of zinc-dependent endopeptidases which specifically degrade components of the extracellular matrix (ECM). Therefore, MMPs have mainly been implicated in various diseases accompanied with an altered turnover of ECM. Besides the altered synthesis of single ECM components the increased expression and/or activity of MMPs seems of paramount importance for pathological remodeling processes within the kidney such as acute proliferative glomerulonephritis (1, 2). Mainly the altered expression of MMP-2 and MMP-9, which are also denoted as gelatinases, is crucially involved in the progression of glomerular inflammatory processes (2, 3). In addition to various inflammatory cytokines, the expression of MMP-9 can be activated by many other stimuli such as mitogens, growth factors, and activators of the Ras oncogene (for review, see Refs. 4 and 5). Although most of these stimuli can modulate gelatinolytic activity by influencing MMP-9 gene expression, the regulation of MMP-9 activity is also achieved by the processing of the inactive proenzyme by the action of other proteases and by an inhibition of the active enzyme by its endogenous inhibitors, the tissue inhibitors of MMPs (4,5). Previously, we have demonstrated an additional mode of posttranscript...

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“…Altered gene expression results from the induction of several redox-sensitive transcription factors (including NFkB, AP-1, and HIF-1) and the oxidation, nitration, and nitrosation of the potential 500 kinases and 200 phosphatases contained in the cells of the human kidney (23,91,176,181,233,234). Oxidative stress downregulates protein tyrosine phosphatases, while upregulating protein tyrosine kinases, including JNK and p42/p44 (ERK-1/ERK-2) mitogen-activated protein kinase (MAPK) pathways (23,123,130,151,290), although nitric oxide-induced activation of soluble guanylate cyclase and generation of cGMP triggers phosphorylation events that may counteract some of these effects.…”

Section: Ros-induced Gene Expression and Fibrosismentioning

confidence: 99%

Oxidant Mechanisms in Renal Injury and Disease

Ratliff

Abdulmahdi

Pawar

et al. 2016

Antioxidants & Redox Signaling

559

513

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Significance: A common link between all forms of acute and chronic kidney injuries, regardless of species, is enhanced generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) during injury/ disease progression. While low levels of ROS and RNS are required for prosurvival signaling, cell proliferation and growth, and vasoreactivity regulation, an imbalance of ROS and RNS generation and elimination leads to inflammation, cell death, tissue damage, and disease/injury progression. Recent Advances: Many aspects of renal oxidative stress still require investigation, including clarification of the mechanisms which prompt ROS/ RNS generation and subsequent renal damage. However, we currently have a basic understanding of the major features of oxidative stress pathology and its link to kidney injury/disease, which this review summarizes. Critical Issues: The review summarizes the critical sources of oxidative stress in the kidney during injury/ disease, including generation of ROS and RNS from mitochondria, NADPH oxidase, and inducible nitric oxide synthase. The review next summarizes the renal antioxidant systems that protect against oxidative stress, including superoxide dismutase and catalase, the glutathione and thioredoxin systems, and others. Next, we describe how oxidative stress affects kidney function and promotes damage in every nephron segment, including the renal vessels, glomeruli, and tubules. Future Directions: Despite the limited success associated with the application of antioxidants for treatment of kidney injury/disease thus far, preventing the generation and accumulation of ROS and RNS provides an ideal target for potential therapeutic treatments. The review discusses the shortcomings of antioxidant treatments previously used and the potential promise of new ones.

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Stimulation by extracellular ATP and UTP of the stress‐activated protein kinase cascade in rat renal mesangial cells

Cited by 43 publications

References 56 publications

Adenosine 5′-triphosphate stimulates the increase of TGF-β1 in rat mesangial cells under high-glucose conditions via reactive oxygen species and ERK1/2

Adenosine 5′-triphosphate stimulates the increase of TGF-β1 in rat mesangial cells under high-glucose conditions via reactive oxygen species and ERK1/2

ATP Potentiates Interleukin-1β-induced MMP-9 Expression in Mesangial Cells via Recruitment of the ELAV Protein HuR

Oxidant Mechanisms in Renal Injury and Disease

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