L-Carnitine protects against tacrolimus-induced renal injury by attenuating programmed cell death via PI3K/AKT/PTEN signaling

Hai-lan Zheng1, Hai-yue Zhang2, Chun-lian Zhu1, Hui-ying Li1, Sheng Cui1,3, Jian Jin1, Shang-guo Piao1, Yu-ji Jiang1, Mei-ying Xuan1,4, Ji-zhe Jin1, Ying-shun Jin1, Jung-pyo Lee5, Byung-ha Chung3,6, Bum-soon Choi3,6, Chul-woo Yang3,6, Can Li1
1 Department of Nephrology, Yanbian University Hospital, Yanji 133000, China
2 College of Chemical and Life Science, Changchun University of Technology, Changchun 130000, China
3 Transplantation Research Center, Department of Internal Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul 06591, Korea
4 Department of Health Examination Central, Yanbian University, Yanji 133000, China
5 Division of Nephrology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul 07061, Korea
6 Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
Correspondence to: Can Li:,
DOI: 10.1038/s41401-020-0449-8
Received: 7 March 2020
Accepted: 21 May 2020
Advance online: 17 June 2020


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 (200 mg · 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.
Keywords: L-carnitine; tacrolimus nephropathy; oxidative stress; pyroptosis; apoptosis; autophagy; PI3K/AKT/PTEN; HK-2 cells; LY294002

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