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

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.

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