Rhein Inhibits Podocyte Ferroptosis and Epithelial-Mesenchymal Transition in Diabetic Nephropathy by Activating the SIRT1/p53/SLC7A11 Pathway

Objectives: Podocytes undergo epithelial-mesenchymal transition (EMT) and ferroptosis in response to hyperglycemic stimulation. This is considered an important early event in the development and progression of diabetic nephropathy (DN). Rhein is the main active anthraquinone derivative in several common traditional herbal medicines. This study aimed to investigate the protective effects of Rhein on podocyte ferroptosis and EMT. Methods: The mouse glomerular podocyte cell line MPC5 was stimulated with high glucose (HG), Rhein, and the ferroptosis inhibitor ferrostatin-1 (Fer-1). Mechanistic investigations employed plasmids to overexpress and knockdown Sirtuin-1 (SIRT1), solute carrier family 7 member 11 (SLC7A11), or p53 and measure ferroptosis- or EMT-related indicators. Results: In the HG-injured podocytes, Rhein enhanced cell viability, reduced malondialdehyde (MDA), ferrous iron (Fe2+), and reactive oxygen species (ROS) levels, increased glutathione (GSH) production, accompanied by the restoration of ferroptosis- and EMT-associated indicator expressions. Mechanistically, Rhein induced SIRT1 and SLC7A11 expression and attenuated p53 expression. SIRT1 knockdown upregulated p53 and downregulated SLC7A11, thereby abolishing the protective effects of Rhein against podocyte ferroptosis and EMT. However, the effects of SIRT1 overexpression were reversed by SLC7A11 knockdown. Conclusion: Rhein activated the SIRT1/p53/SLC7A11 axis to protect podocytes against ferroptosis and EMT. This suggests that Rhein has a potential therapeutic effect on DN patients associated with podocyte injury, and targeting SIRT1/p53/SLC7A11 may represent an innovative therapeutic strategy for DN patients.