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α2-antiplasmin positively regulates endothelial-to-mesenchymal transition and fibrosis progression in diabetic nephropathy

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Abstract

Background

Diabetic nephropathy (DN), is microvascular complication of diabetes causes to kidney dysfunction and renal fibrosis. It is known that hyperglycemia and advanced glycation end products (AGEs) produced by hyperglycemic condition induce myofibroblast differentiation and endothelial-to-mesenchymal transition (EndoMT), and exacerbate fibrosis in DN. Recently, we demonstrated that α2-antiplasmin (α2AP) is associated with inflammatory response and fibrosis progression.

Methods

We investigated the role of α2AP on fibrosis progression in DN using a streptozotocin-induced DN mouse model.

Results

α2AP deficiency attenuated EndoMT and fibrosis progression in DN model mice. We also showed that the high glucose condition/AGEs induced α2AP production in fibroblasts (FBs), and the reduction of receptor for AGEs (RAGE) by siRNA attenuated the AGEs-induced α2AP production in FBs. Furthermore, the bloackade of α2AP by the neutralizing antibody attenuated the high glucose condition-induced pro-fibrotic changes in FBs. On the other hand, the hyperglycemic condition/AGEs induced EndoMT in vascular endothelial cells (ECs), the FBs/ECs co-culture promoted the high glucose condition-induced EndoMT compared to ECs mono-culture. Furthermore, α2AP promoted the AGEs-induced EndoMT, and the blockade of α2AP attenuated the FBs/ECs co-culture-promoted EndoMT under the high glucose condition.

Conclusions

The high glucose conditions induced α2AP production, and α2AP is associated with EndoMT and fibrosis progression in DN. These findings provide a basis for clinical strategies to improve DN.

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Authors and Affiliations

  1. Department of Molecular Pathology, Faculty of Pharmaceutical Science, Doshisha Women’s College of Liberal Arts, 97-1 Kodo Kyo-tanabe, Kyoto, 610-0395, Japan

    Yosuke Kanno, Momoko Hirota & Kei-ichi Ozaki

  2. Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, 589-8511, Japan

    Osamu Matsuo

Authors
  1. Yosuke Kanno
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  2. Momoko Hirota
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  3. Osamu Matsuo
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  4. Kei-ichi Ozaki
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Contributions

YK conceived and designed the experiment. YK, MH and OM were involved in the mice experiments. YK and MH analyzed the data. YK, OM and KO were involved in data interpretation and writing of the manuscript.

Corresponding author

Correspondence to Yosuke Kanno.

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The authors declare no conflict of interest.

Ethical approval

The mice experiments in this study were approved by the Animal Research Committee of Doshisha Women’s College of Liberal Arts (Approval ID: Y17-015), and were carried out in accordance with the rules and regulations of the institutions and the government.

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Kanno, Y., Hirota, M., Matsuo, O. et al. α2-antiplasmin positively regulates endothelial-to-mesenchymal transition and fibrosis progression in diabetic nephropathy. Mol Biol Rep 49, 205–215 (2022). https://doi.org/10.1007/s11033-021-06859-z

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  • DOI: https://doi.org/10.1007/s11033-021-06859-z

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