Objective:To explore the effect of knockdown of Sig-1R on endoplasmic reticulum stress and podocyte injury. Methods: siRNA vectors for silencing Sig-1R were constructed and transfected into mouse podocyte clones(MPC5), which were divided into normal control, negative control and interference groups. The mRNA and protein expressions of Sig-1R were detected by real-time PCR and Western blot, respectively. The apoptosis of podocytes was detected by nuclear staining using Hochest 33258. The protein expressions of nephrin, desmin, bcl-2, bax, caspase-3, 8, 9, 12 were detected by Western blot. Results:The reducation of Sig-1R in mRNA and protein levels was detected when the podocytes were transfected with Sig-1R siRNA(P < 0.05). The expression of nephrin decreased, while the expression of desmin increased significantly(P < 0.05) compared to control. The apoptosis of podocyte was exhibited in the interference group. The expression of bcl-2 markedly decreased, while the expression of bax increased, and the ratio of bcl-2 to bax was less than 1/2.(P < 0.05). The expression of active caspase-3 and caspase-12 increased significantly(P < 0.05), while the expression of pro-caspase 9 decreased and pro caspase 8 had no change. Conclusion:The knockdown of Sig-1R can cause endoplasmic reticulum stress and podocyte injury.