Objective: Exploring the effects of miR-155 regulation of SMAD2 expression in podocyte injury as well as macrophage inflammatory response in mouse lupus nephritis. Methods: The experimental mice were randomly divided into blank, model, AAV9-miR-NC, AAV9-miR-155, AAV9-miR-anti, and AAV9-miR-anti-NC groups, with 8 mice in each group, of which the blank group was C57BL/6 mice, and the rest of the groups were MRL/lpr mice, and the groups were treated and sampled accordingly. The presence or absence of a binding site for miR-155 and SMAD2 was predicted by target genes, an online target gene prediction website. Dual luciferase reporter gene analysis system to validate the targeting relationship between miR-155 and SMAD2. Determination of 24 h urinary protein content in each group of mice by Caumas Brilliant Blue method. Hematoxylin-Eosin staining was used to observe the kidney tissues of mice ; qRT-PCR to detect the expression level of miR-155 in kidney tissues of each group. Western blot was used to detect nephrin, P-cadherin and SMAD2 protein expression in renal tissues. Immunofluorescence assay to detect the expression of inflammatory factors (IL-6, TNF-α) in mice. Results: Compared with the blank group, mice in the model group had elevated urinary protein, severe renal pathological damage, and decreased expression levels of nephrin, P-cadherin, and SMAD2 while increased expression levels of IL-6 and TNF-α in renal tissues (P<0.05). Compared with the model group and AAV9-miR-NC group, mice in the model group of AAV9- miR-155 group showed elevated urinary protein, obvious renal pathological damage, and obvious elevation of miR-155 in renal tissues, whereas the expression levels of nephrin, P-cadherin, and SMAD2 were decreased (P<0.05) whereas the fluorescence intensity of IL-6 and TNF-α was enhanced significantly; Compared with the model and AAV9-miR-anti-NC groups, mice in the AAV9-miR-anti group showed decreased urinary protein, improved renal pathological injury, decreased miR-155 expression, and increased expression levels of nephrin, P-cadherin, and SMAD2 compared to the model group (P<0.05) whereas the fluorescence intensities of IL-6 and TNF-α decreased; In the model group, AAV9-miR-NC group, and AAV9-miR-anti-NC group mice, the differences in the above indexes were not statistically significant (P>0.05). Dual luciferase reporter gene assay showed that miR-155 inhibited the fluorescence activity of wild-type SMAD2 cells and targeted the regulation of SMAD2 expression. Conclusion: High expression of miR-155 exacerbated podocyte injury and inflammatory response in lupus nephritis in mice by regulating SMAD2, whereas inhibition of miR-155 expression attenuated podocyte injury and inflammatory response in mice. [ABSTRACT FROM AUTHOR]