Abstract 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.
Du et al. (Sat,) studied this question.
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