AIM: To investigate the effect of drug-containing serum of oxytropis falcata extract on oxidative stress injury of podocyte induced by high glucose through PI3K/AKT/Nrf2 pathway. METHODS:The rat renal podocyte was cultured in vitro, and the concentration and time of D-glucose modelling and the optimal concentration and time of administration in the drug-containing serum of oxytropis falcata extract were screened. The cells were divided into normal group, high glucose group, high glucose+blank serum group, oxytropis falcata group, inhibitor group, oxytropis falcata+inhibitor group. Rhodamine staining and electron microscopy were used to observe the morphological and pathological changes of podocyte, flow cytometry was used to detect apoptosis rate, and cell migration ability was detected by scratch test. Immunofluorescence and fluorescence probe were used to detect the fluorescence expression of p-AKT and ROS level of cells, ELISA was used to detect the content of MDA, NO, SOD and T-AOC in the supernatant of cells, and Western Blot was used to detect the protein expression of p-PI3K/PI3K, p-AKT/AKT and Nrf2 in cells.The mRNA expressions of Nrf2, HO-1, GCLM and SOD were detected by RT-qPCR. RESULTS: It was selected that 45 mmol/LD-glucose induction for 48 hours was the best modeling condition, and the 1-fold dilution of the medicated serum of oxytropis falcata extract for 48 hours was the best concentration and intervention time. Compared with the normal group, the foot processes of the high glucose group were widely fused and adhered to each other, the apoptosis rate, migration ability and intracellular ROS level were significantly increased (P<0.01), the fluorescence expression of p-AKT was markedly decreased (P<0.01), the contents of MDA and NO were dramatically enhanced, and the contents of SOD and T-AOC were significantly downregulated (P<0.01). The protein expression of p-PI3K/PI3K, p-AKT/AKT, Nrf2 and the mRNA expression of Nrf2, HO-1, GCLM and SOD markedly declined (P<0.01). Compared with high glucose group, foot process fusion and adhesion of podocytes in oxytropis falcata group and oxytropis falcata + inhibitor group were improved in varying degrees, apoptosis rate, migration ability and intracellular ROS level significantly declined (P<0.05, P<0.01), p-AKT fluorescence expression increased (P<0.01), NO content decreased, T-AOC level elevated (P<0.01); the content of MDA decreased and the activity of SOD notably rose (P<0.01), the protein expression of p-PI3K/PI3K, p-AKT/AKT, Nrf2 and the mRNA expression of Nrf2, HO-1, GCLM and SOD markedly increased in oxytropis falcata group (P<0.05, P<0.01); the level of ROS in podocytes improved (P<0.01), the fluorescence expression of p-AKT decreased (P<0.05), the content of NO upregulated, the content of T-AOC downregulated, and the expression of p-PI3K/PI3K, p-AKT/AKT, Nrf2 protein and HO-1, GCLM, SOD mRNA decreased in inhibitor group (P<0.05, P<0.01). Compared with oxytropis falcata group, the apoptosis rate, migration ability and intracellular ROS level of podocytes in oxytropis falcata + inhibitor group markedly increased (P<0.05, P<0.01), p-AKT fluorescence expression declined (P<0.01), MDA and NO content increased, SOD and T-AOC content decreased (P<0.05, P<0.01), p-PI3K/PI3K, p-AKT/AKT, Nrf2 protein and Nrf2, HO-1, GCLM, SOD mRNA expression all dramatically downregulated (P<0.05, P<0.01). CONCLUSION: Oxytropis falcata extract may protect podocytes by activating the PI3K/AKT/Nrf2 signaling pathway, thereby improving the morphological, structural and functional changes of podocytes induced by high glucose and inhibiting oxidative stress response.