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Klotho inhibits the formation of calcium oxalate stones by regulating the Keap1-Nrf2-ARE signaling pathway

  • Urology - Original Paper
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Abstract

Purpose

Oxidative damage is important in calcium oxalate (CaOx) stone development but occurs via multiple pathways. Studies have shown that klotho plays an essential role in ameliorating oxidative damage. This study aims to explore the role of klotho in CaOx stones and whether the underlying mechanism is related to the regulation of Keap1-Nrf2-ARE signaling.Methods.

Methods

The levels of GSH, SOD, CAT, MDA, and ROS were examined by ELISA. The klotho, Bcl-2, caspase-3, Keap1, Nrf2, HO-1, and NQO1 mRNA levels were measured by qRT‒PCR, and their protein levels were detected by Western blotting. Renal tissue apoptosis was examined by TUNEL staining, and crystal cell adherence and apoptosis in HKC cells were assessed based on the Ca2+ concentrations and by flow cytometry. The renal pathological changes and the adhesion of CaOx crystals in the kidneys were examined by hematoxylin–eosin and von Kossa staining, respectively.Results.

Results

We constructed a CaOx kidney stone model in vitro. By regulating the klotho gene, klotho overexpression inhibited the CaOx‐induced promotion of crystal cell adherence and apoptosis in HKC cells, and these effects were reversed by klotho knockdown. Moreover, our in vivo assay demonstrated that klotho overexpression alleviated glyoxylate administration-induced renal oxidative damage, renal apoptosis, and crystal deposition in the kidneys of mice, and these effects were also associated with activation of the Keap1-Nrf2-ARE pathway.Conclusion.

Conclusion

Klotho protein inhibits the oxidative stress response of HKC cells through the Keap1-Nrf2-ARE signaling pathway, reduces the apoptosis of and adhesion of CaOx crystals to HKC cells, and decreases the occurrence of CaOx kidney stones.

Clinical trial registration

20220304.

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Data availability

The data used to support the findings of this study are included within the article.

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Funding

This work was supported by National Natural Science Foundation of China (Name of the fund: The role and Mechanism of Klotho protein in calcium oxalate stone formation by regulating Kear1-Nrf2-ARE signal Pathway No. 81760128).

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Authors and Affiliations

  1. Department of Urology, Second Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China

    Bahtiyar Ahmatjan, Liu ruotian & Murat Mahmut

  2. Department of Urology, Second Affiliated Hospital of Xinjiang Medical University, Urumqi, 830036, China

    Alim rahman & Murat Mahmut

  3. Department of Urology, Xinjiang Medical University, Urumqi, 830011, China

    ma bin & Du heng

  4. Department of Urology, Second Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China

    He yi, Cui tao & Gao le

Authors
  1. Bahtiyar Ahmatjan
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  2. Liu ruotian
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  3. Alim rahman
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  4. ma bin
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  5. Du heng
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  6. He yi
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  7. Cui tao
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  8. Gao le
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  9. Murat Mahmut
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Contributions

This study was performed in collaboration with all authors. Murat Mahmut and Ma Bin conceived the outline and designed the study. Liu Ruo Tian and Murat Mahmut revised the manuscript. All the authors reviewed and approved the final version of the manuscript.

Corresponding author

Correspondence to Murat Mahmut.

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All authors declare that there are no conflicts of interest.

Ethical approval

This study was approved by the Ethics Committee of The Second Affiliated Hospital of Xinjiang Medical University (Urumqi, China).

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Ahmatjan, B., ruotian, L., rahman, A. et al. Klotho inhibits the formation of calcium oxalate stones by regulating the Keap1-Nrf2-ARE signaling pathway. Int Urol Nephrol 55, 263–276 (2023). https://doi.org/10.1007/s11255-022-03398-9

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  • DOI: https://doi.org/10.1007/s11255-022-03398-9

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