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Reducing immunosuppressant-related complications using conventional drugs is an efficient therapeutic strategy.L-carnitine(LC)has been shown to protect against various types of renal injury.In this study,we investigated the renoprotective effects of LC in a rat model of chronic tacrolimus(TAC)nephropathy.SD rats were injected with TAC(1.5 mg ? kg-1 ? d-1,sc)for 4 weeks.Renoprotective effects of LC were assessed in terms of renal function,histopathology,oxidative stress,expression of inflammatory and fibrotic cytokines,programmed cell death(pyroptosis,apoptosis,and autophagy),mitochondrial function,and PI3K/AKT/PTEN signaling.Chronic TAC nephropathy was characterized by severe renal dysfunction and typical histological features of chronic nephropathy.At a molecular level,TAC markedly increased the expression of inflammatory and fibrotic cytokines in the kidney,induced oxidative stress,and led to mitochondrial dysfunction and programmed cell death through activation of PI3K/AKT and inhibition of PTEN.Coadministration of LC(200mg·kg-1·d-1,ip)caused a prominent improvement in renal function and ameliorated histological changes of kidneys in TAC-treated rats.Furthermore,LC exerted anti-inflammatory and antioxidant effects,prevented mitochondrial dysfunction,and modulated the expression of a series of apoptosis-and autophagy-controlling genes to promote cell survival.Human kidney proximal tubular epithelial cells(HK-2 cells)were treated with TAC(50 μg/mL)in vitro,which induced production of intracellular reactive oxygen species and expression of an array of genes controlling programmed cell death(pyroptosis,apoptosis,and autophagy)through interfering with PI3K/AKT/PTEN signaling.The harmful responses of HK-2 cells to TAC were significantly attenuated by cotreatment with LC and the PI3K inhibitor LY294002(25 μM).In conclusion,LC treatment protects against chronic TAC nephropathy through interfering the PI3K/AKT/PTEN signaling.