Urinary exosomes aggravate diabetic kidney disease by inducing podocyte ferroptosis via the miR‐217/SIRT1/Nrf2 pathway

Urinary exosomal microRNAs (miRNAs) mediate intercellular communication in diabetic kidney disease (DKD), a leading contributor to end-stage renal failure. However, the involvement of urinary exosomal miR-217 in DKD remains poorly understood. Urinary exosomes were characterized, and miR-217 expression was measured in clinical samples. The miR-217/SIRT1 interaction was validated by dual-luciferase assays. Podocyte viability, ferroptosis-related markers, and protein expression were assessed in vitro, whereas renal function and histology were evaluated in a streptozotocin-induced DKD mouse model. MiR-217 was upregulated in urinary exosomes derived from patients with DKD. Inhibition of miR-217 alleviated exosome-induced podocyte injury, lipid peroxidation, and ferroptosis, and preserved podocyte markers; these protective effects can be partially reversed by Fer-1 or miR-217 inhibition. SIRT1 was confirmed to be a direct target of miR-217, which negatively regulated SIRT1 expression and suppressed the SIRT1/Nrf2 pathway. SIRT1 knockdown abolished the protective effects of miR-217 inhibition. Conversely, miR-217 mimic exacerbated ferroptotic damage and downregulated the expression of podocyte markers, which were partly rescued by SIRT1 overexpression. In vivo, miR-217 inhibition attenuated DKD-exosome-aggravated kidney injury and ferroptosis, whereas SIRT1 inhibition abrogated this protective effect. Collectively, these findings indicate that urinary exosomal miR-217 promotes podocyte ferroptosis and DKD progression via suppression of the SIRT1/Nrf2 pathway, suggesting a potential therapeutic target for DKD.