Journal
LIFE SCIENCES
Volume 272, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2021.119119
Keywords
Acute kidney injury; Autologous orthotopic liver transplantation; FoxO3a; PI3K/AKT; SIRT1; Phosphorylation; Deacetylation
Funding
- National Natural Science Foundation of China [81571926, 81770649, 81772127, 81974296]
- Science and Technology Planning Project of Guangdong Province of China [2020A0505100035]
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The study showed that activation of the PI3K/AKT signaling pathway can attenuate post-AOLT AKI by regulating the expression of apoptosis-related proteins and facilitating cell deacetylation to protect renal function.
Aims: Acute kidney injury (AKI) is a severe complication of autologous orthotopic liver transplantation (AOLT). Apoptosis has been shown to be involved in renal ischemia/reperfusion, and the PI3K/AKT signaling pathway is involved in numerous cell processes, including promoting cell survival and inhibiting apoptosis. We aimed to verify whether the PI3K/AKT signaling pathway participates in the development of post-AOLT AKI. Methods: Male Sprague-Dawley rats underwent AOLT with or without treatment with insulin-like growth factor-1 (IGF-1, a PI3K/AKT activator) and LY294002 (a PI3K/AKT inhibitor; n = 8/group). NRK-52E cells (rat renal tubular epithelial cell line) were subjected to hypoxia-re-oxygenation to mimic renal cell I/R injury in vitro, and confirm whether silencing information regulator 1 (SIRT1) mediated the protective effects of PI3K/AKT by deacetylating forkhead protein O3a (FoxO3a). Key findings: During the reperfusion stage, kidney injury peaked at 8 h after reperfusion, then gradually recovered, which was consistent with the dynamic changes in apoptosis and the protein expressions of Bcl-2 interacting mediator of cell death (Bim), Fas ligand (FasL), and nuclear FoxO3a AKT phosphorylation and nuclear SIRT1 protein expression were also upregulated. IGF-1 application decreased Bim, FasL, and nuclear FoxO3a protein expressions, and protected against apoptosis and AKI. In NRK-52E cells, IGF-1 upregulated nuclear SIRT1 expression, reduced FoxO3a acetylation, downregulated Bim and FasL protein expressions, and attenuated apoptosis and AKI; these effects were reversed by SIRT1 blocking. Conclusion: The activation of the PI3K/AKT signaling pathway not only induced FoxO3a nuclear export but also deacetylation through upregulating nuclear SIRT1 expression to attenuate post-AOLT AKI.
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