Anti-renal interstitial fibrosis effect of norcantharidin is exerted through inhibition of PP2Ac-mediated C-terminal phosphorylation of Smad3

doi:10.1111/cbdd.13781

. 2021 Feb;97(2):293-304.

doi: 10.1111/cbdd.13781. Epub 2020 Sep 7.

Anti-renal interstitial fibrosis effect of norcantharidin is exerted through inhibition of PP2Ac-mediated C-terminal phosphorylation of Smad3

Han-Wen Luo¹, Dan-Dan Yin², Zheng Xiao¹, Lu Wen¹, Ying-Jun Liao¹, Cheng-Yuan Tang¹, Dong Zeng¹, Heng-Ting Xiao¹, Ying Li¹

Affiliations

¹ Department of Nephrology, Key Laboratory of Kidney Disease and Blood Purification in Hunan, The Second Xiangya Hospital, Central South University, Hunan, China.
² Jiangsu Province Hospital, Nanjing Medical University First Affiliated Hospital Nanjing, Jiangsu, China.

PMID: 32896083
DOI: 10.1111/cbdd.13781

Anti-renal interstitial fibrosis effect of norcantharidin is exerted through inhibition of PP2Ac-mediated C-terminal phosphorylation of Smad3

Han-Wen Luo et al. Chem Biol Drug Des. 2021 Feb.

. 2021 Feb;97(2):293-304.

doi: 10.1111/cbdd.13781. Epub 2020 Sep 7.

Authors

Han-Wen Luo¹, Dan-Dan Yin², Zheng Xiao¹, Lu Wen¹, Ying-Jun Liao¹, Cheng-Yuan Tang¹, Dong Zeng¹, Heng-Ting Xiao¹, Ying Li¹

Affiliations

¹ Department of Nephrology, Key Laboratory of Kidney Disease and Blood Purification in Hunan, The Second Xiangya Hospital, Central South University, Hunan, China.
² Jiangsu Province Hospital, Nanjing Medical University First Affiliated Hospital Nanjing, Jiangsu, China.

PMID: 32896083
DOI: 10.1111/cbdd.13781

Abstract

Norcantharidin (NCTD), the demethylated analog of cantharidin isolated from Mylabris, is known to inhibit renal fibrosis. However, the underlying mechanism is largely unknown. The present study investigates whether NCTD exerts this effect through regulation of the protein phosphatase 2A catalytic subunit (PP2Ac)-Smad3 pathway. HK-2 human renal proximal tubule cells exposed to transforming growth factor (TGF)-β1 were used as an in vitro model of renal fibrosis. The levels of total Smad3, C-terminal-phosphorylated Smad3 (p-Smad3), PP2Ac, and fibronectin (Fn) were evaluated by Western blotting. A PP2Ac overexpression plasmid and the PP2Ac inhibitor okadaic acid (OA) were used for functional analyses. The subcellular localization of Smad3 was visualized by immunofluorescence labeling. The results showed that PP2Ac overexpression increased Smad3 phosphorylation and nuclear translocation in HK-2 cells, while pharmacologic inhibition of PP2Ac with OA had the opposite effect. NCTD suppressed Fn and p-Smad3 expression and TGF-β1-induced nuclear entry of Smad3, but these effects were abrogated by inhibition of PP2Ac. Thus, the anti-renal interstitial fibrosis effect of NCTD is exerted through inhibition of PP2Ac-mediated C-terminal phosphorylation of Smad3. These findings highlight the therapeutic potential of NCTD for the treatment of renal interstitial fibrosis.

Keywords: Smad3 C-terminus; norcantharidin; protein phosphatase 2A catalytic subunit; renal interstitial fibrosis.

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References

REFERENCES

1. Ai, J., Nie, J., He, J., Guo, Q., Li, M., Lei, Y., … Hou, F. F. (2015). GQ5 hinders renal fibrosis in obstructive nephropathy by selectively inhibiting TGF-β-induced Smad3 phosphorylation. Journal of the American Society of Nephrology, 26, 1827-1838. https://doi.org/10.1681/ASN.2014040363
1. Bengtsson, L., Schwappacher, R., Roth, M., Boergermann, J. H., Hassel, S., & Knaus, P. (2009). PP2A regulates BMP signalling by interacting with BMP receptor complexes and by dephosphorylating both the C-terminus and the linker region of Smad1. Journal of Cell Science, 122, 1248-1257. https://doi.org/10.1242/jcs.039552
1. Chen, L., Yang, T., Lu, D. W., Zhao, H., Feng, Y. L., Chen, H., … Zhao, Y. Y. (2018). Central role of dysregulation of TGF-beta/Smad in CKD progression and potential targets of its treatment. Biomedicine and Pharmacotherapy, 101, 670-681. https://doi.org/10.1016/j.biopha.2018.02.090
1. Deng, L., & Tang, S. (2011). Norcantharidin analogues: A patent review (2006-2010). Expert Opinion on Therapeutic Patents, 21, 1743-1753. https://doi.org/10.1517/13543776.2011.629190
1. Deng, Y., Cai, Y., Liu, L., Lin, X., Lu, P., Guo, Y., … Xu, G. (2019). Blocking Tyr265 nitration of protein phosphatase 2A attenuates nitrosative stress-induced endothelial dysfunction in renal microvessels. The FASEB Journal, 33, 3718-3730. https://doi.org/10.1096/fj.201800885RR

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[1] Ai, J., Nie, J., He, J., Guo, Q., Li, M., Lei, Y., … Hou, F. F. (2015). GQ5 hinders renal fibrosis in obstructive nephropathy by selectively inhibiting TGF-β-induced Smad3 phosphorylation. Journal of the American Society of Nephrology, 26, 1827-1838. https://doi.org/10.1681/ASN.2014040363

[2] Ai, J., Nie, J., He, J., Guo, Q., Li, M., Lei, Y., … Hou, F. F. (2015). GQ5 hinders renal fibrosis in obstructive nephropathy by selectively inhibiting TGF-β-induced Smad3 phosphorylation. Journal of the American Society of Nephrology, 26, 1827-1838. https://doi.org/10.1681/ASN.2014040363

[3] Bengtsson, L., Schwappacher, R., Roth, M., Boergermann, J. H., Hassel, S., & Knaus, P. (2009). PP2A regulates BMP signalling by interacting with BMP receptor complexes and by dephosphorylating both the C-terminus and the linker region of Smad1. Journal of Cell Science, 122, 1248-1257. https://doi.org/10.1242/jcs.039552

[4] Bengtsson, L., Schwappacher, R., Roth, M., Boergermann, J. H., Hassel, S., & Knaus, P. (2009). PP2A regulates BMP signalling by interacting with BMP receptor complexes and by dephosphorylating both the C-terminus and the linker region of Smad1. Journal of Cell Science, 122, 1248-1257. https://doi.org/10.1242/jcs.039552

[5] Chen, L., Yang, T., Lu, D. W., Zhao, H., Feng, Y. L., Chen, H., … Zhao, Y. Y. (2018). Central role of dysregulation of TGF-beta/Smad in CKD progression and potential targets of its treatment. Biomedicine and Pharmacotherapy, 101, 670-681. https://doi.org/10.1016/j.biopha.2018.02.090

[6] Chen, L., Yang, T., Lu, D. W., Zhao, H., Feng, Y. L., Chen, H., … Zhao, Y. Y. (2018). Central role of dysregulation of TGF-beta/Smad in CKD progression and potential targets of its treatment. Biomedicine and Pharmacotherapy, 101, 670-681. https://doi.org/10.1016/j.biopha.2018.02.090

[7] Deng, L., & Tang, S. (2011). Norcantharidin analogues: A patent review (2006-2010). Expert Opinion on Therapeutic Patents, 21, 1743-1753. https://doi.org/10.1517/13543776.2011.629190

[8] Deng, L., & Tang, S. (2011). Norcantharidin analogues: A patent review (2006-2010). Expert Opinion on Therapeutic Patents, 21, 1743-1753. https://doi.org/10.1517/13543776.2011.629190

[9] Deng, Y., Cai, Y., Liu, L., Lin, X., Lu, P., Guo, Y., … Xu, G. (2019). Blocking Tyr265 nitration of protein phosphatase 2A attenuates nitrosative stress-induced endothelial dysfunction in renal microvessels. The FASEB Journal, 33, 3718-3730. https://doi.org/10.1096/fj.201800885RR

[10] Deng, Y., Cai, Y., Liu, L., Lin, X., Lu, P., Guo, Y., … Xu, G. (2019). Blocking Tyr265 nitration of protein phosphatase 2A attenuates nitrosative stress-induced endothelial dysfunction in renal microvessels. The FASEB Journal, 33, 3718-3730. https://doi.org/10.1096/fj.201800885RR

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Anti-renal interstitial fibrosis effect of norcantharidin is exerted through inhibition of PP2Ac-mediated C-terminal phosphorylation of Smad3

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Anti-renal interstitial fibrosis effect of norcantharidin is exerted through inhibition of PP2Ac-mediated C-terminal phosphorylation of Smad3

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