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Dapagliflozin, the Sodium-glucose cotransporter 2 (SGLT2) inhibitor class of glucose-lowering agents, has shown the significantly nephroprotective effects to reduce the risk of kidney failure in diabetes. However, the underlying mechanisms are incompletely understood to explain the beneficial effects of dapagliflozin on kidney function. Here, we demonstrated that the administered of dapagliflozin for 12 weeks improved the proteinuria, histomorphology damage, oxidative stress, and macrophage infiltrations in the kidney of streptozotocin (STZ)-induced diabetic mice. Meanwhile, dapagliflozin attenuated the renal inflammation and fibrosis by reducing the pro-inflammatory factors interleukin-6 (IL-6), IL-1β, and tumor necrosis factor α (TNF-α) and anti-fiber factor fibronectin (FN) and elevating the anti-inflammatory factor IL-10. Our data revealed that dapagliflozin exerted anti-inflammatory effects by inhibiting the activation of high mobility group box 1 (HMGB1)/TLR2/4/NF-κB signaling pathway. Consistently, we found that dapagliflozin suppressed the expression of HMGB1 and downstream TLR2/4/NF-κB signaling proteins in the human proximal tubular (HK-2) stimulated by high glucose and lipids or HMGB1 and RAW264.7 cells stimulated by IL-1β, respectively. Further experiments were performed in the indirect co-culture model of RAW264.7 and HK-2 cells induced by high glucose and lipids. The results again confirmed the effects of dapagliflozin on alleviating inflammatory response and regulating the proportions of M1/M2 macrophage. It is indicated that the feedback signaling of HMGB1 between the tubules and macrophage involves in the persistence of the inflammation. These data demonstrate that dapagliflozin suppress the self-perpetuating inflammation by blocking the feedback loop of HMGB1 in the kidney, which contribute to ameliorate the renal injury in diabetes. [Display omitted] • Dapagliflozin attenuates the inflammatory response of diabetic kidney tissue. • Dapagliflozin suppresses the activation of HMGB1 mediated TLR2/4/NF-κB signaling pathway. • The nephroprotective effect of dapagliflozin is associated with blocking HMGB1 feedback loop of kidney. [ABSTRACT FROM AUTHOR]