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Angiotensin II induces calcium/calcineurin signaling and podocyte injury by downregulating microRNA-30 family members

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Abstract

Angiotensin II (AngII) is capable of inducing calcium/calcineurin signaling and podocyte injury; however, the precise underlying mechanism is not well understood. Because we have previously demonstrated that microRNA-30s (miR-30s) inhibit calcium/calcineurin signaling in podocytes, we hypothesize that AngII may induce podocyte injury by downregulating miR-30s and thereby activating calcium/calcineurin signaling. To test this hypothesis, we used an AngII-induced podocyte injury mouse model. The mice were treated with AngII via infusion for 28 days, which resulted in hypertension, albuminuria, and glomerular damage. AngII treatment also resulted in a significant reduction of miR-30s and upregulation of calcium/calcineurin signaling components, including TRPC6, PPP3CA, PPP3CB, PPP3R1, and NFATC3, which are the known targets of miR-30s in podocytes. The delivery of miR-30a-expressing lentivirus to the podocytes on day 14 of the infusion ameliorated the AngII-induced podocyte and glomerular injury and attenuated the upregulation of the calcium/calcineurin signaling components. Similarly, treatment with losartan, which is an AngII receptor blocker, also prevented AngII-induced podocyte injury and calcium/calcineurin signaling activation. Notably, losartan was found to sustain miR-30 levels during AngII treatment both in vivo and in vitro. In conclusion, the effect of AngII on podocytes is in part mediated by miR-30s through calcium/calcineurin signaling, a novel mechanism underlying AngII-induced podocyte injury.

Key messages

• AngII infusion resulted in downregulation of miR-30s in podocytes.

• Exogenous miR-30a delivery mitigated the glomerular and podocyte injuries induced by AngII.

• Both miR-30a and losartan prevented AngII-induced activation of calcium-calcineurin signaling.

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Acknowledgments

This work was supported by the Major International (Regional) Joint Research Project (81320108007), the Major Research Plan of the National Natural Science Foundation (91442104), and grants from the National Natural Science Foundation of China (81600559, 81500549) and a research grant from **ling Hospital, Nan**g University School of Medicine (2016035).

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Author notes

  1. Yue Zhao and Junnan Wu contributed equally to this work.

Authors and Affiliations

  1. National Clinical Research Center of Kidney Diseases, **ling Hospital, Nan**g University School of Medicine, Nan**g, Jiangsu, 210002, China

    Yue Zhao, Junnan Wu, Mingchao Zhang, Minlin Zhou, Feng Xu, **aodong Zhu, **anguang Zhou, Yue Lang, Fan Yang, Shaolin Shi & Zhihong Liu

  2. Comparative Medicine Department, **ling Hospital, Nan**g University School of Medicine, Nan**g, Jiangsu, 210002, China

    Shifeng Yun

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  1. Yue Zhao
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  11. Shaolin Shi
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Contributions

Y.Z., Z.L., and SS designed the study. J.W., Y.Z., M.Z. (M Zhang), X.Z. (X Zhu), X.Z. (X Zhou),Y.L., and F.Y. performed the experiments. Y.Z. and M.Z. (M Zhou) did data statistics. F.X. did the mesangial expansion quantification. Y.Z. and S.Y. analyzed mouse data. Y.Z., Z.L., and S.S. wrote the manuscript. All authors have reviewed and approved the final version of manuscript.

Corresponding authors

Correspondence to Shaolin Shi or Zhihong Liu.

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Zhao, Y., Wu, J., Zhang, M. et al. Angiotensin II induces calcium/calcineurin signaling and podocyte injury by downregulating microRNA-30 family members. J Mol Med 95, 887–898 (2017). https://doi.org/10.1007/s00109-017-1547-z

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  • DOI: https://doi.org/10.1007/s00109-017-1547-z

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