Lithospermic acid improves diabetic kidney fibrosis by regulating Piezo1/TGF-β1/Smad signaling pathway

  • Eur J Pharmacol. 2025 Sep 15:1003:177896. doi: 10.1016/j.ejphar.2025.177896.
Yameng Yan  1 ,  Cuifen Wang  1 ,  Shangfei Luo  1 ,  Tianying Hong  1 ,  Weipin Niu  1 ,  Xin Sun  1 ,  Enmeng Zhang  1 ,  Mei Yang  1 ,  Zheng Li  1 ,  Jiali Liu  1 ,  Zhijuan Zheng  2 ,  Jing Li  3
Affiliations
  • 1. Innovation Research Center, Shandong University of Chinese Medicine, Jinan, 250307, China.
  • 2. Innovation Research Center, Shandong University of Chinese Medicine, Jinan, 250307, China. Electronic address: [email protected].
  • 3. Innovation Research Center, Shandong University of Chinese Medicine, Jinan, 250307, China; The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China. Electronic address: [email protected].
PMID: 40609618 DOI: 10.1016/j.ejphar.2025.177896
Abstract

Background: Diabetic kidney disease (DKD) stands as a prominent complication of diabetes, with renal tubulointerstitial fibrosis playing a crucial role in its progression towards end-stage renal disease. Piezo1, a mechanosensitive, non-selective CA2+ channel, has been definitively linked to the progression of kidney fibrosis.

Purpose: The objective of this research is to investigate the pharmacological effects and the underlying mechanisms of lithospermic acid (LA), a polycyclic phenolic carboxylic acid derived from Salvia miltiorrhiza, on DKD-related fibrosis.

Methods and results: To evaluate the protective effect of LA on DKD against renal fibrosis, mice were treated with streptozotocin (STZ) for 7 consecutive days to establish a type 1 diabetes mellitus (T1DM) model. Following the successful establishment of the T1DM model, LA was intraperitoneally administered for an additional 8 weeks. LA significantly attenuated fibrosis formation, inhibited epithelial-mesenchymal transition (EMT) and suppressed the expression of Piezo1 in DKD. In addition, LA decreased activation and expression of Piezo1 in human kidney-2 (HK-2) cells treated with high glucose conditions or Yoda1. Mechanistically, transforming growth factor-β1 (TGF-β1) signaling pathway regulated by Piezo1/CA2+ axis was attenuated following LA treatment.

Conclusion: In summary, our research uncovered the promising potential of LA in mitigating kidney fibrosis, a complication arising from diabetes, through the inhibition of Piezo1. Furthermore, it underscored the pivotal role that Piezo1 plays in the underlying mechanisms leading to renal fibrosis in DKD.

Keywords
Epithelial-mesenchymal transition; Piezo1; Renal fibrosis; T1DM; lithospermic acid.
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