Abstract: Objective To investigate the expression and signifcance of Synaptopodin resulting in podocyte injury in high-fat diet C57BL/6J mice. Methods Thirty-two male C57BL/6J mice were randomly divided into two groups. The standard group was fed with basic diet and high-fat diet group was fed with high-fat diet for 4 weeks. Body weight and urine protein changes were measured. nsulin resistance was detected by glucose tolerance test. The kidney tissue morphological changes were examined by HE staining. The expression of Synaptopodin was examined by immunohistochemistry and western blotting. Results In high-fat diet group, the body weight was higher than the standard group, and there was signifcant decrease in glucose tolerance levels and rise in urinary lbumin/ creatinine ratio. HE staining results showed that there were glomeruli hypertrophy, mesangial matrix hyperplasia, and glomerulosclerosis. Compared with standard group, the expression of Synaptopodin in high-fat diet group reduced signifcantly in odocyte. Conclusion The expression of Synaptopodin in podocyte of high-fat diet C57BL/6J mice reduces signifcantly, which may ead to proteinuria.