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Indoxyl sulphate-TNFα axis mediates uremic encephalopathy in rodent acute kidney injury

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Acute kidney injury (AKI) is often accompanied by uremic encephalopathy resulting from accumulation of uremic toxins in brain possibly due to impaired blood-brain barrier (BBB) function. Anionic uremic toxins are substrates or inhibitors of organic anionic transporters (OATs). In this study we investigated the CNS behaviors and expression/function of BBB OAT3 in AKI rats and mice, which received intraperitoneal injection of cisplatin 8 and 20 mg/kg, respectively. We showed that cisplatin treatment significantly inhibited the expressions of OAT3, synaptophysin and microtubule-associated protein 2 (MAP2), impaired locomotor and exploration activities, and increased accumulation of uremic toxins in the brain of AKI rats and mice. In vitro studies showed that uremic toxins neither alter OAT3 expression in human cerebral microvascular endothelial cells, nor synaptophysin and MAP2 expressions in human neuroblastoma (SH-SY5Y) cells. In contrast, tumour necrosis factor alpha (TNFα) and the conditioned medium (CM) from RAW264.7 cells treated with indoxyl sulfate (IS) significantly impaired OAT3 expression. TNFα and CM from IS-treated BV-2 cells also inhibited synaptophysin and MAP2 expressions in SH-SY5Y cells. The alterations caused by TNFα and CMs in vitro, and by AKI and TNFα in vivo were abolished by infliximab, a monoclonal antibody designed to intercept and neutralize TNFα, suggesting that AKI impaired the expressions of OAT3, synaptophysin and MAP2 in the brain via IS-induced TNFα release from macrophages or microglia (termed as IS-TNFα axis). Treatment of mice with TNFα (0.5 mg·kg−1·d−1, i.p. for 3 days) significantly increased p-p65 expression and reduced the expressions of Nrf2 and HO-1. Inhibiting NF-κB pathway, silencing p65, or activating Nrf2 and HO-1 obviously attenuated TNFα-induced downregulation of OAT3, synaptophysin and MAP2 expressions. Significantly increased p-p65 and decreased Nrf2 and HO-1 protein levels were also detected in brain of AKI mice and rats. We conclude that AKI inhibits the expressions of OAT3, synaptophysin and MAP2 due to IS-induced TNFα release from macrophages or microglia. TNFα impairs the expressions of OAT3, synaptophysin and MAP2 partly via activating NF-κB pathway and inhibiting Nrf2-HO-1 pathway.

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Fig. 1: Psychiatry behaviors in the open field test and Y-maze test, levels of plasma and brain uremic toxins as well as function of OAT3 at BBB of CON and AKI rats.
Fig. 2: Effect of AKI on psychiatry behaviors, function and expression of OAT3 in brain of mice.
Fig. 3: Roles of IS-TNFα axis in downregulation of OAT3 in hCMEC/D3 cells and rBMECs.
Fig. 4: Transport of bumetanide and IS across hCMEC/D3 monolayers.
Fig. 5: Roles of IS-TNFα axis in downregulated expressions of SYN and MAP2 proteins in SH-SY5Y cells.
Fig. 6: Study on signaling pathways of decreased expressions of synaptophysin and MAP2 proteins mediated by TNFα in SH-SY5Y cells.
Fig. 7: Effects of IS and infliximab on psychiatric behaviors and expressions of OAT3, synaptophysin and MAP2 proteins in BBB of mice.
Fig. 8: Effect of TNFα on psychiatry behaviors, function and expression of OAT3 in brain of mice.
Fig. 9: Effect of infliximab on psychiatric behaviors and expressions of OAT3, synaptophysin and MAP2 proteins in BBB of mice.
Fig. 10: Effect of infliximab on behaviors, function and expression of brain OAT3 in AKI rats.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82373943, 82173844, 82204511, and 82073922) and the Jiangsu Funding Program for Excellent Postdoctoral Talent (No. 1412200067).

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Authors and Affiliations

  1. Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China

    Ling Jiang, Xue-ying Sun, Si-qian Wang, Yan-lin Liu, Ling-jue Lu, Wen-han Wu, Hao Zhi, Zhong-yan Wang, Xiao-dong Liu & Li Liu

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  1. Ling Jiang
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Contributions

LL, XDL, LJ carried out the ideas and designed the studies; LJ, XYS, SQW, YLL, LJL, HZ, ZYW conducted the experiments, acquired the data and documented data analysis; XYS, WHW interpreted results and plotted figures; LJ, LL, XDL drafted, revised and approved the final version of the manuscript.

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Correspondence to Xiao-dong Liu or Li Liu.

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Jiang, L., Sun, Xy., Wang, Sq. et al. Indoxyl sulphate-TNFα axis mediates uremic encephalopathy in rodent acute kidney injury. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01251-6

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