Objective To investigate the role of miRNA-455-3p in the process of glomerulosclerosis in rats with diabetic kidney disease (DKD) and the intervention effect of irbesartan. Methods Intervention experiment of miRNA-455-3p agonist:there were 18 male SD rats, 6 of which were randomly selected as normal control group, and the other 12 rats were fed with high-fat and high-sugar diet and intraperitoneally injected with streptozotocin (STZ) to prepare DKD models. After successful modeling, they were randomly divided into model group (STZ group) and overexpression miRNA-455-3p group (STZ+miRNA-455-3p group), with 6 rats in each group. In the STZ+miRNA-455-3p group, miRNA-455-3p agonist was injected intraperitoneally at a dose of 20 mg/kg at the second and fifth weeks after STZ injection. Irbesartan intervention experiment:18 male SD rats were divided into normal control group, model group (STZ group) and irbesartan intervention group (STZ+irbesartan group), with 6 rats in each group. The STZ+irbesartan group was gavaged with 50 mg/kg irbesartan suspension. The 24-h urine volume and 24-h urine protein levels were recorded after 12 weeks. The expression levels of miRNA-455-3p in sera and kidney tissues were detected by qRT-PCR. The pathological changes of rat kidney tissues were observed by periodic acid Schiff staining, and the expression levels of collagenⅠand proliferating cell nuclear antigen (PCNA) were detected by Western blotting. Results The 24-h urine volume and 24-h urine protein levels of rats in the STZ+miRNA-455-3p and STZ+irbesartan groups were significantly lower than those in the STZ groups (all P<0.05); the expression levels of miRNA-455-3p in sera and kidney tissues of rats in the STZ+miRNA-455-3p and STZ+irbesartan groups were significantly higher than those of the STZ groups (all P<0.05); and the expression levels of collagenⅠand PCNA in the kidney tissues of rats in the STZ+miRNA-455-3p and STZ+irbesartan groups were significantly lower than those in the STZ groups. Conclusion miRNA-455-3p participates in the process of DKD and may be a new target for DKD treatment, and irbesartan can delay the process of DKD glomerulosclerosis by regulating miRNA-455-3p.