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Diabetic kidney disease(DKD) has become the leading cause of end-stage renal disease and the main cause of death of chronic kidney disease. Renal interstitial fibrosis is an important pathological change of DKD, and chronic microinflammation also plays a key role in the occurrence and development of Diabetic Nephropathy(DN). Macrophages are one of the main regulatory cells of inflammation and infiltrate in the kidney tissue of early DN. In addition to producing injury mediators, activated macrophages can also affect the kidney through other mechanisms. Interestingly, there are a large amount of exosomes generated by macrophage under hyperglycemia condition and it is not clear whether the exosomes has any effect on glomerular mesangial cell fibrosis in patients with diabetes. Here, we use a diabetic nephropathy db/db mouse model to determine the effect of macrophage-produced exosomes by miR-146a-5p overexpression or down-regulation on mesangial cell fibrosis. with high glucose, Macrophage proliferation is promoted in mice and miR-146a-5p expression is downregulated in both macrophages and glomerular mesangial cells. we confirmed that Smad4 is the target gene of miR-146a-5p through Luciferase reporter gene system. Fibrosis-associated col I, α-SMA, and Smad4 are upregulated in glomerular mesangial cells. In exosomes, we observed miR-146a-5p is downregulated in high glucose than low glucose. We use the exosomes from the macrophages that are transfected with miR-146a-5p mimics or inhibitor to culture the glomerular mesangial cells. Exosomes from miR-146a-5p mimics significantly downregulated glomerular Mesangial cell fibrosis-related factor α-SMA, col I protein, and Smad4. Exosomes from miR-146a-5p inhibition upregulated these factors. Finally, we found macrophage exosomes from miR-146a-5p overexpression can inhibit glomerular mesangial cell fibrosis, which could provide a potential treatment strategy for DKD. Disclosure W. Zhang: None. H. Jiang: None. Y. Ma: None. H. Peng: None. J. Liu: None. J. Yuan: None. K. Hu: None. B. Zhao: None. H. Wu: None.