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mPGES-1-derived prostaglandin E2 stimulates Stat3 to promote podocyte apoptosis

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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.

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Acknowledgements

This work was supported by Grants from the National Natural Science Foundation of China (Nos. 81600557, 81600532, 81600352, 81370802, 81300591, 81670647, and 81570616), the National Key Research and Development Program (No. 2016YFC0906103), and the Natural Science Foundation of Jiangsu Province (Nos. BK2012001, BK20160136, BK20160137). We thank Dr. Yue Zhang for her support on some experimental techniques.

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  1. Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, 210008, People’s Republic of China

    Jing Yu, Yimei Wu, Lu Wang, Wen Zhang, Man Xu, Jiayu Song, Yu Fu, Yiyun Cui, Wei Gong, Shuzhen Li, Weiwei Xia, Songming Huang, Aihua Zhang & Zhanjun Jia

  2. Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, People’s Republic of China

    Jing Yu, Yimei Wu, Lu Wang, Wen Zhang, Man Xu, Jiayu Song, Yu Fu, Yiyun Cui, Wei Gong, Shuzhen Li, Weiwei Xia, Songming Huang, Aihua Zhang & Zhanjun Jia

  3. Nanjing Key Laboratory of Pediatrics, Nanjing Medical University (Children’s Hospital of Nanjing Medical University), Nanjing, 210008, People’s Republic of China

    Jing Yu, Yimei Wu, Lu Wang, Wen Zhang, Man Xu, Jiayu Song, Yu Fu, Yiyun Cui, Wei Gong, Shuzhen Li, Weiwei Xia, Songming Huang, Aihua Zhang & Zhanjun Jia

  4. Department of Nephrology, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210029, Jiangsu, People’s Republic of China

    Zhanjun Jia

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  1. Jing Yu
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  2. Yimei Wu
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  3. Lu Wang
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  5. Man Xu
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  7. Yu Fu
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  9. Wei Gong
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  11. Weiwei Xia
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  14. Zhanjun Jia
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Correspondence to Zhanjun Jia.

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Yu, J., Wu, Y., Wang, L. et al. mPGES-1-derived prostaglandin E2 stimulates Stat3 to promote podocyte apoptosis. Apoptosis 22, 1431–1440 (2017). https://doi.org/10.1007/s10495-017-1418-7

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  • DOI: https://doi.org/10.1007/s10495-017-1418-7

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