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Triptolide Alleviates Podocyte Epithelial-Mesenchymal Transition via Kindlin-2 and EMT-Related TGF-β/Smad Signaling Pathway in Diabetic Kidney Disease

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Abstract

Diabetes-induced chronic kidney diseases are widespread and decrease the quality of life for millions of affected individuals in China. To date, no therapies effectively alleviate these conditions. Triptolide, a traditionally used Chinese medicine, has shown promise in treating renal diseases. Here, the study aimed to decipher the exact mechanism by which it functions. It was hypothesized that triptolide might prevent the epithelial-mesenchymal transition (EMT) of podocytes by activating the kindlin-2 and TGF-β/Smad pathways. Triptolide or telmisartan was intragastrically administered to 9-week-old db/db and dm/dm mice with diabetic nephropathy (DN) for 12 weeks. In addition, biochemical parameters and body weight were detected. WT-1, nephrin, podocin, E-cadherin, and α-SMA were determined by immunohistochemistry in the renal tissues of treated mice. Protein and mRNA expression of podocyte EMT markers, kindlin-2 and TGF-β/Smad, were analyzed to elucidate the underlying mechanism. It was observed that triptolide treatment relieved structural injuries and functional variations in diabetic mice. It also increased the protein and mRNA levels of nephrin, podocin, and E-cadherin and decreased the expression of α-SMA in diabetic mice. The protein and mRNA expressions of TGF-β1, p-SMAD3, and kindlin-2 decreased in diabetic kidneys following triptolide treatment. The findings demonstrated that triptolide might protect podocytes during DN by inhibiting podocyte EMT through inactivation of kindlin-2, combined with the downregulation of P-SMAD3 in the TGF-β/Smad signaling pathway.

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Funding

This study was financially supported by the Huzhou Municipal Science and Technology Bureau Public Welfare Application Research Project (grant No. 2017GY23, 2020GY17); Zhejiang Medical and Health Science and Technology Project (grant No. 2021KY1093); Zhejiang Science and Technology Planning Project (grant No. 2017C37106); Zhejiang Medical and Health Science and Technology Project (Grant No. 2016KYA172); and Zhejiang Medical and Health Science and Technology Project (Grant No. 2017KY639).

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Authors and Affiliations

  1. Department of Nephrology, the First Affiliated Hospital of Huzhou Teachers College, the First People’s Hospital of Huzhou, Huzhou, Zhejiang, 313000, People’s Republic of China

    Lingyan Ren, Ming Zhu, Yong Yang, Qi Chen & Xiaoyi Wang

  2. Department of General Surgery, Huzhou Central Hospital, Huzhou, Zhejiang, 313000, People’s Republic of China

    Renrui Wan

  3. Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, School of Medicine, Huzhou University, Huzhou, Zhejiang, 313000, People’s Republic of China

    Zheng Chen

  4. Department of Central Laboratory, the First Affiliated Hospital of Huzhou Teachers College, the First People’s Hospital of Huzhou, Huzhou, Zhejiang, 313000, People’s Republic of China

    Lixia Huo

  5. Department of Pathology, the First Affiliated Hospital of Huzhou Teachers College, the First People’s Hospital of Huzhou, Huzhou, Zhejiang, 313000, People’s Republic of China

    Xiaolan Zhang

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  1. Lingyan Ren
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  2. Renrui Wan
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  3. Zheng Chen
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  4. Lixia Huo
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  5. Ming Zhu
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  6. Yong Yang
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  7. Qi Chen
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  8. Xiaolan Zhang
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  9. Xiaoyi Wang
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Authors contributed equally.

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Correspondence to Xiaoyi Wang.

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Ren, L., Wan, R., Chen, Z. et al. Triptolide Alleviates Podocyte Epithelial-Mesenchymal Transition via Kindlin-2 and EMT-Related TGF-β/Smad Signaling Pathway in Diabetic Kidney Disease. Appl Biochem Biotechnol 194, 1000–1012 (2022). https://doi.org/10.1007/s12010-021-03661-2

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  • DOI: https://doi.org/10.1007/s12010-021-03661-2

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