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Erythropoietin promotes energy metabolism to improve LPS-induced injury in HK-2 cells via SIRT1/PGC1-α pathway

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Abstract

Acute kidney injury (AKI) is one of frequent complications of sepsis with high mortality. Mitochondria is the center of energy metabolism participating in the pathogenesis of sepsis-associated AKI, and SIRT1/PGC1-α signaling pathway plays a crucial role in the modulation of energy metabolism. Erythropoietin (EPO) exerts protective functions on chronic kidney disease. We aimed to assess the effects of EPO on cell damage and energy metabolism in a cell model of septic AKI. Renal tubular epithelial cells HK-2 were treated with LPS and human recombinant erythropoietin (rhEPO). Cell viability was detected by CCK-8 and mitochondrial membrane potential was determined using JC-1 fluorescent probe. Then the content of ATP, ADP and NADPH, as well as lactic acid, were measured for the assessment of energy metabolism. Oxidative stress was evaluated by detecting the levels of ROS, MDA, SOD and GSH. Pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, were measured with ELISA. Moreover, qRT-PCR and western blot were performed to detect mRNA and protein expressions. shSIRT1 was used to knockdown SIRT1, while EX527 and SR-18292 were applied to inhibit SIRT1 and PGC1-α, respectively, to investigate the regulatory mechanism of rhEPO on inflammatory injury and energy metabolism. In LPS-exposed HK-2 cells, rhEPO attenuated cell damage, inflammation and abnormal energy metabolism, as indicated by the elevated cell viability, the inhibited oxidative stress, cell apoptosis and inflammation, as well as the increased mitochondrial membrane potential and energy metabolism. However, these protective effects induced by rhEPO were reversed after SIRT1 or PGC1-α inhibition. EPO activated SIRT1/PGC1-α pathway to alleviate LPS-induced abnormal energy metabolism and cell damage in HK-2 cells. Our study suggested that rhEPO played a renoprotective role through SIRT1/PGC1-α pathway, which supported its therapeutic potential in septic AKI.

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The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

Thanks to the members of our laboratory for their contributions.

Funding

This work was supported by National Natural Science Foundation of Gansu Province (Grant No. 20JR5RA350), Innovation and Entrepreneurship Action Plan Project for students of the First Clinical Medical School of Lanzhou University, and Excellence Program Project for students of the First Clinical Medical School of Lanzhou University.

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  1. Kan Li, Li Gao and Sen Zhou are all first co-authors.

Authors and Affiliations

  1. Department of Nephrology, The First Hospital of Lanzhou University, No.1 Donggangxi Road, Chengguan District, Lanzhou, 730000, Gansu Province, China

    Kan Li, Sen Zhou, Ming-Long Liu & Tian-Xi Liu

  2. Department of Gynaecology, The First Hospital of Lanzhou University, Lanzhou, 730000, Gansu Province, China

    Li Gao

  3. Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, 730000, Gansu Province, China

    Yan-Rong Ma

  4. The First Clinical Medical School of Lanzhou University, Lanzhou, 730000, Gansu Province, China

    Xiao Xiao, Qian Jiang & Zhi-Hong Kang

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Contributions

KL: concepts, design, experimental studies, writing—original draft preparation, supervision. LG: data analysis. SZ: experimental studies. Y-RM: data analysis. XX: experimental studies. QJ: data acquisition. Z-HK: data acquisition. M-LL: writing—reviewing and editing. T-XL: writing—reviewing and editing, funding acquisition, supervision. All the authors approved for the final version.

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Correspondence to Tian-Xi Liu.

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Supplementary file1 Effect of rhEPO on HK-2 cell viability (TIF 919 KB)

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Li, K., Gao, L., Zhou, S. et al. Erythropoietin promotes energy metabolism to improve LPS-induced injury in HK-2 cells via SIRT1/PGC1-α pathway. Mol Cell Biochem 478, 651–663 (2023). https://doi.org/10.1007/s11010-022-04540-y

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