Klotho activation of Nrf2 inhibits the ferroptosis signaling pathway to ameliorate sepsis-associated acute kidney injury

Pan Zhou; Congcong Zhao; Yuhong Chen; Xuefang Liu; Chunxue Wu; Zhenjie Hu

doi:10.21037/tau-23-573

Klotho activation of Nrf2 inhibits the ferroptosis signaling pathway to ameliorate sepsis-associated acute kidney injury

Transl Androl Urol. 2023 Dec 31;12(12):1871-1884. doi: 10.21037/tau-23-573. Epub 2023 Dec 21.

Authors

Pan Zhou¹, Congcong Zhao¹, Yuhong Chen^{1

2}, Xuefang Liu³, Chunxue Wu⁴, Zhenjie Hu^{1

2}

Affiliations

¹ Department of Critical Care Medicine, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
² Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, China.
³ Department of Anesthesiology and Intensive Care Unit, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
⁴ Intensive Care Unit of Emergency Department, Neurology Branch of Cangzhou Central Hospital, Cangzhou, China.

Abstract

Background: Sepsis-associated acute kidney injury (SA-AKI) is a common complication of sepsis and greatly increases patient mortality. Recombinant human Klotho protein (Klotho) is a protective protein that can be secreted by the kidney. The aim of this study was to explore the protective effect of Klotho on SA-AKI and its molecular mechanism.

Methods: In vivo, a mouse SA-AKI model was constructed by cecum ligation perforation (CLP). In vitro, a human renal tubular cell epithelial cell line (HK2) was induced with lipopolysaccharide (LPS) in the SA-AKI model. Determine renal injury markers, inflammatory factors, oxidative stress and molecular proteins related to the ferroptosis signaling pathway.

Results: Klotho reduced the release of renal injury markers and inflammatory cytokines, decreased oxidative stress, improved renal histopathological changes, ameliorated mitochondrial damage in mouse renal tubular epithelial cells, increased HK2 cell viability and reduced reactive oxygen species (ROS) accumulation. Exogenous supplementation with Klotho increased the Klotho content in circulating blood, renal tissue and HK2 cells.

Conclusions: In the SA-AKI model, Klotho attenuated renal tissue injury, increased HK2 cell viability, decreased inflammatory factor expression and oxidative stress, restored tubular epithelial mitochondrial function, and increased its level in circulating blood, renal tissue and HK2 cells. Klotho probably exerts its protective effects by activating Nrf2 to inhibit the ferroptosis signaling pathway.

Keywords: Klotho; Sepsis-associated acute kidney injury (SA-AKI); ferroptosis; oxidative stress.