Open Access

Senolytic combination of dasatinib and quercetin protects against diabetic kidney disease by activating autophagy to alleviate podocyte dedifferentiation via the Notch pathway

  • Authors:
    • Xinwang Zhu
    • Congxiao Zhang
    • Linlin Liu
    • Li Xu
    • Li Yao
  • View Affiliations

  • Published online on: January 17, 2024     https://doi.org/10.3892/ijmm.2024.5350
  • Article Number: 26
  • Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The senolytics dasatinib and quercetin (DQ) alleviate age‑related disorders. However, limited information is available regarding the effects of DQ on diabetic kidney disease (DKD). The present study aimed to explore the effects of DQ on DKD and its potential molecular mechanism(s). Dasatinib (5 mg/kg) and quercetin (50 mg/kg) were administered to diabetic db/db mice by gavage for 20 weeks. Body weight, urine albumin‑creatinine ratio (ACR), serum creatinine (Scr), and blood urea nitrogen (BUN) were recorded at the indicated time periods. Periodic acid‑Schiff and Masson's staining were performed to assess the histopathological changes of kidney tissues. Immunohistochemical analysis, immunofluorescence and western blotting were performed to evaluate the expression levels of extracellular matrix (ECM) proteins, autophagic and podocyte differentiation‑related proteins. In addition, mouse podocytes were administered with high‑glucose, DQ and 3‑methyladenine (3‑MA), and the expression levels of autophagic and podocyte differentiation‑related proteins were measured. Moreover, following overexpression of the Notch intracellular domain (NICD), the expression levels of NICD, autophagic and podocyte differentiation‑related proteins were further assessed. DQ significantly reduced the body weight, blood glucose, ACR, Scr and BUN levels and improved the histopathological changes induced in diabetic db/db mice. In addition, DQ caused a significant downregulation of the expression levels of the ECM proteins, improved autophagy and induced an upregulation of the expression levels of podocyte differentiation‑related proteins. Administration of 3‑MA to mice significantly reduced podocyte differentiation, and overexpression of NICD could reverse the effects of DQ on autophagy and podocyte differentiation in vitro. The present study suggests that DQ protects against DKD by activation of autophagy to alleviate podocyte dedifferentiation via the Notch pathway.
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March-2024
Volume 53 Issue 3

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Zhu X, Zhang C, Liu L, Xu L and Yao L: Senolytic combination of dasatinib and quercetin protects against diabetic kidney disease by activating autophagy to alleviate podocyte dedifferentiation via the Notch pathway. Int J Mol Med 53: 26, 2024.
APA
Zhu, X., Zhang, C., Liu, L., Xu, L., & Yao, L. (2024). Senolytic combination of dasatinib and quercetin protects against diabetic kidney disease by activating autophagy to alleviate podocyte dedifferentiation via the Notch pathway. International Journal of Molecular Medicine, 53, 26. https://doi.org/10.3892/ijmm.2024.5350
MLA
Zhu, X., Zhang, C., Liu, L., Xu, L., Yao, L."Senolytic combination of dasatinib and quercetin protects against diabetic kidney disease by activating autophagy to alleviate podocyte dedifferentiation via the Notch pathway". International Journal of Molecular Medicine 53.3 (2024): 26.
Chicago
Zhu, X., Zhang, C., Liu, L., Xu, L., Yao, L."Senolytic combination of dasatinib and quercetin protects against diabetic kidney disease by activating autophagy to alleviate podocyte dedifferentiation via the Notch pathway". International Journal of Molecular Medicine 53, no. 3 (2024): 26. https://doi.org/10.3892/ijmm.2024.5350