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Sestrin2 attenuates renal damage by regulating Hippo pathway in diabetic nephropathy

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Abstract

Glomerular mesangial cell proliferation and extracellular matrix accumulation contribute to the progression of diabetic nephropathy (DN). As a conserved stress-inducible protein, sestrin2 (Sesn2) plays critical role in the regulation of oxidative stress, inflammation, autophagy, metabolism, and endoplasmic reticulum stress. In this study, we investigated the role of Sesn2 on renal damage in diabetic kidney using transgenic mice overexpressing Sesn2 and the effect of Sesn2 on mesangial cell proliferation and extracellular matrix accumulation in diabetic conditions and the possible molecular mechanisms involved. Sesn2 overexpression improved renal function and decreased glomerular hypertrophy, albuminuria, mesangial expansion, extracellular matrix accumulation, and TGF-β1 expression, as well as oxidative stress in diabetic mice. In vitro experiments, using human mesangial cells (HMCs), revealed that Sesn2 overexpression inhibited high glucose (HG)-induced proliferation, fibronectin and collagen IV production, and ROS generation. Meanwhile, Sesn2 overexpression restored phosphorylation levels of Lats1 and YAP and inhibited TEAD1 expression. Inhibition of Lats1 accelerated HG-induced proliferation and expression of fibronectin and collagen IV. Verteporfin, an inhibitor of YAP, suppressed HG-induced proliferation and expression of fibronectin and collagen IV. However, Sesn2 overexpression reversed Lats1 deficiency-induced Lats1 and YAP phosphorylation, nuclear expression levels of YAP and TEAD1, and proliferation and fibronectin and collagen IV expressions in HMCs exposed to HG. In addition, antioxidant NAC or tempol treatment promoted phosphorylation of Lats1 and YAP and inhibited TEAD1 expression, proliferation, and fibronectin and collagen IV accumulation in HG-treated HMCs. Taken together, Sesn2 overexpression inhibited mesangial cell proliferation and fibrosis via regulating Hippo pathway in diabetic nephropathy. Induction of Sesn2 may be a potential therapeutic target in diabetic nephropathy.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81470966), the Funds for Guiding Local Scientific and Technological Development by the Central Government of China (216Z7703G), and the Natural Science Foundation of Hebei Province (No. H2021206144; H2021206356).

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Authors and Affiliations

  1. Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, China

    Yawei Bian, Chonglin Shi, Shan Song, Lin Mu, Ming Wu, Duojun Qiu, Jiajia Dong, Wei Zhang, Chen Yuan, Dongyun Wang, Zihui Zhou, Xuan Dong & Yonghong Shi

  2. Hebei Key Laboratory of Kidney Disease, Shijiazhuang, 050017, China

    Shan Song, Lin Mu, Xuan Dong & Yonghong Shi

  3. Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, 050017, China

    Shan Song & Yonghong Shi

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  1. Yawei Bian
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  2. Chonglin Shi
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  3. Shan Song
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  4. Lin Mu
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  5. Ming Wu
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  9. Chen Yuan
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  10. Dongyun Wang
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  11. Zihui Zhou
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  12. Xuan Dong
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  13. Yonghong Shi
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Contributions

Yawei Bian, Shan Song, and Yonghong Shi contributed to the conception and design of the study. Yawei Bian, Chonglin Shi, Ming Wu, Jiajia Dong, and Xuan Dong were responsible for the execution of the cell experiments. Shan Song, Duojun Qiu, and Dongyun Wang were responsible for the animal experiments. Lin Mu, Wei Zhang, Zihui Zhou, and Chen Yuan were responsible in the assistance of the completion of animal experiments. Yawei Bian and Yonghong Shi were responsible for writing and editing the manuscript.

Corresponding author

Correspondence to Yonghong Shi.

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All experimental animal procedures were reviewed and approved by Ethics Review Committee for Animal Experimentation of Hebei Medical University (No. IACUC-Hebmu-2021030). Clinical specimens were approved by Hebei Medical University ethical committees (No. 20190015).

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The authors declare no competing interests.

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Bian, Y., Shi, C., Song, S. et al. Sestrin2 attenuates renal damage by regulating Hippo pathway in diabetic nephropathy. Cell Tissue Res 390, 93–112 (2022). https://doi.org/10.1007/s00441-022-03668-z

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