Objective To investigate the action mechanism of Gli2, a key transcription factor in the Hedgehog pathway, in renal tubular lesions of cisplatin-induced acute kidney injury (AKI). Methods (1) Animal experiments: Male SD rats were randomly divided into a control group (injection with saline) or a model group (single intraperitoneal injection with cisplatin, 15 mg/kg). The followings were compared between the two groups: serum creatinine levels before and 1, 3, and 5 days after the injection, pathological changes in renal tissues 5 days after the injection, and relative expression levels of mRNAs and proteins of Gli2, Shh, α-SMA, TGF-β1, NGAL, IL-6, IL-18 (Hedgehog pathway factors and markers of renal tubular injury and fibrosis) and Caspase7 (marker of cell apoptosis) 5 days after the injection. (2) Cellular experiments: Impacts of different concentrations of cisplatin (0, 12.5, or 25 μmol/L) on relative expression levels of Gli2 mRNA and and Gli2 protein in NRK-52E cells were analyzed after the 24-hour intervention. Concentration was chosen to build cell models for subsequent experiments based on the abovementioned concertration gradient tests' results. The rat renal tubular epithelial cells, NRK-52E, were divided into a silent empty vector control group (treated with 12.5 μmol/L cisplatin for 24 hours) or a Gli2-silenced group (using the shRNA method). The relative expression levels of mRNAs and proteins of Gli2, NGAL, Smo, TGF-β1, α-SMA (Hedgehog pathway factors and markers of renal tubular injury and fibrosis), as well as Bax and Caspase7 (markers of cell apoptosis), were compared between the two groups of NRK-52E cells. Results (1) Animal experiments: The model group showed higher serum creatinine levels than the control group 1, 3, and 5 days after the injection (all P<0.05), and the level increased in a time-dependent way. Renal histopathology showed typical characteristics of renal tubular lesions, including exposure of the basilar membrane due to epithelial cell shedding, interstitial infiltration by inflammatory cells, vacuolar degeneration, and fibrotic changes. After 5 days of injection, the relative expression levels of Gli2, Shh, α-SMA, TGF-β1, NGAL, IL-6, IL-18, and Caspase7 mRNAs and proteins in the renal tissues of rats in the model group were all higher than those in the control group (all P<0.05). (2) Cell experiment: With the increase of cisplatin intervention concentration, the relative expression levels of Gli2 mRNA and Gli2 protein in NRK-52E cells gradually increased (all P<0.05). After 24 hours of intervention with cisplatin at a concentration of 12.5 μmol/L, the relative expression levels of Gli2, NGAL, Smo, TGF-β1, α-SMA, Bax, and Caspase7 mRNAs and proteins in the NRK-52E cells of the Gli2-silenced group, as well as the early apoptosis rate, late apoptosis rate, and total apoptosis rate of the NRK-52E cells, were all lower than those in the silent empty vector control group (all P<0.05). Conclusion The Hedgehog/Gli2 pathway is activated in cisplatin-induced AKI. Gli2 mediates renal tubular epithelial cell injury, apoptosis, and fibrosis in AKI by regulating the activity of the Hedgehog/Gli2 pathway. Gli2 inhibitors are expected to become effective drugs for treating AKI fibrosis and blocking its chronic transformation. 

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