Dysfunction of mesangial cells plays a significant role in the glomerular lesions and is implicated in the pathophysiology of diabetic nephropathy (DN). Macrophages infiltration is the main pathological feature of DN, which can ultimately lead to renal inflammation. Recent studies suggest that the crosstalk between kidney resident cells and inflammatory cells influences the development of DN, and that controlling this crosstalk may help treat DN. Here, we found that DN mice appeared renal pathological damage, including dilation of mesangial matrix and significant infiltration of macrophages, accompanied by increased inflammatory response, NLRP3 inflammasome activation and autophagy deficiency. Additionally, mesangial cells internalized exosomes from high glucose (HG) treated macrophage, resulting the activation of inflammatory cytokines and NLRP3 inflammasome and deficiency of autophagy in vitro and in vivo. Moreover, C57BL/6 mice injected HG-stimulated macrophages-derived exosomes exhibited renal dysfunction and mesangial matrix expansion. Taken together, the present study demonstrated that mesangial cells responded to HG treated macrophage-derived exosomes by promoting the activation of NLRP3 inflammasome and autophagy deficiency, thereby participating in the development of DN.Copyright © 2023. Published by Elsevier Inc.