Renal tubular injury and innate immune responses induced by hypoxia contribute to acute kidney injury. Accumulating evidence suggests that miR-21 overexpression protects against kidney ischemia injury. Additionally, miR-21 emerges as a key inhibitor in dendritic cell maturation. Thus, we hypothesized that miR-21 protects the kidney from IR injury by suppressing epithelial cell damage and inflammatory reaction. In this study, we investigated effects of miR-21 and its signaling pathways (PTEN/AKT/mTOR/HIF, PDCD4/NF kappa-B) on kidney ischemia/reperfusion (IR) injury in vitro and in vivo. The results revealed that IR increased miR-21, HIF1 alpha, and 2 alpha expression in vivo and in vitro. MiR-21 interacted with HIF1 alpha and 2 alpha through the PTEN/AKT/mTOR pathway. Moreover, inhibition of miR-21 activated PDCD4/NF kappa-B pathways, which are critical for dendritic cell maturation. Renal IR triggers local inflammation by inducing the dendritic cell maturation and promoting the secretion of IL-12, IL-6, and TNF-alpha cytokines. Knockdown of miR-21 intensified the effect of IR on tubular epithelial cell apoptosis and dendritic cell maturation. Our results suggested that IR-inducible miR-21 protects epithelial cells from IR injury via a feedback interaction with HIF (PTEN/AKT/mTOR/HIF/miR-21) and by inhibiting maturation of DCs through the PDCD4/NF-kappa B pathway. These findings highlight new therapeutic opportunities in AKI.
[1]Fudan Univ, Zhongshan Hosp, Div Nephrol, Shanghai, Peoples R China.
[2]Shanghai Med Ctr Kidney, Shanghai, Peoples R China.
[3]Shanghai Inst Kidney & Dialysis, Shanghai, Peoples R China.
[4]Shanghai Key Lab Kidney & Blood Purificat, Shanghai, Peoples R China.
[5]Hemodialysis Qual Control Ctr Shanghai, Shanghai, Peoples R China.
(8.0+极速模式)