Abstract
We previously reported that microsomal prostaglandin E synthase-1 (mPGES-1) contributed to adriamycin (Adr)-induced podocyte apoptosis. However, the molecular mechanism remains unclear. Here we studied the role of mPGES-1/PGE2 cascade in activating Stat3 signaling and the contribution of Stat3 in PGE2- and Adr-induced podocyte apoptosis. In murine podocytes, PGE2 dose- and time-dependently increased the phosphorylation of Stat3 in line with the enhanced cell apoptosis and reduced podocyte protein podocin. In agreement with the increased Stat3 phosphorylation, Stat3-derived cytokines including IL-6, IL-17, MCP-1, and ICAM-1 were significantly upregulated following PGE2 treatment. By application of a specific Stat3 inhibitor S3I-201, PGE2-induced podocyte apoptosis was largely abolished in parallel with a blockade of podocin reduction. Next, we observed that Adr treatment also enhanced p-Stat3 and activated mPGES-1/PGE2 cascade. Blockade of Stat3 by S3I-201 significantly ameliorated Adr-induced cell apoptosis and podocin reduction. More interestingly, silencing mPGES-1 in podocytes by mPGES-1 siRNA blocked Adr-induced increments of Stat-3 phosphorylation, PGE2 production, and Stat3-derived inflammatory cytokines. Taken together, this study suggested that mPGES-1-derived PGE2 could activate Stat3 signaling to promote podocyte apoptosis. Targeting mPGES-1/PGE2/Stat3 signaling might be a potential strategy for the treatment of podocytopathy.
Keywords:
Adriamycin; PGE2; Podocyte apoptosis; Stat3; mPGES-1.
MeSH terms
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Aminosalicylic Acids / pharmacology
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics*
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Benzenesulfonates / pharmacology
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Cell Line, Transformed
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Chemokine CCL2 / genetics
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Chemokine CCL2 / metabolism
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Dinoprostone / biosynthesis
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Dinoprostone / pharmacology*
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Dose-Response Relationship, Drug
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Doxorubicin / pharmacology
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Gene Expression Regulation
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Intercellular Adhesion Molecule-1 / genetics
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Intercellular Adhesion Molecule-1 / metabolism
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Interleukin-17 / genetics
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Interleukin-17 / metabolism
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Phosphorylation / drug effects
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Podocytes / cytology
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Podocytes / drug effects*
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Podocytes / metabolism
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Prostaglandin-E Synthases / antagonists & inhibitors
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Prostaglandin-E Synthases / genetics*
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Prostaglandin-E Synthases / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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STAT3 Transcription Factor / agonists
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STAT3 Transcription Factor / antagonists & inhibitors
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STAT3 Transcription Factor / genetics*
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STAT3 Transcription Factor / metabolism
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Signal Transduction
Substances
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Aminosalicylic Acids
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Benzenesulfonates
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Ccl2 protein, mouse
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Chemokine CCL2
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Interleukin-17
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Interleukin-6
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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NPHS2 protein
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NSC 74859
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RNA, Small Interfering
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STAT3 Transcription Factor
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Stat3 protein, mouse
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interleukin-6, mouse
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Intercellular Adhesion Molecule-1
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Doxorubicin
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Prostaglandin-E Synthases
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Ptges protein, mouse
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Dinoprostone