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. 2024 Apr 20;51(1):533.
doi: 10.1007/s11033-024-09462-0.

Investigating the role of itaconate in macrophage activation and oxidative stress injury in sepsis-associated acute kidney injury

Lei Yang #  1 , Pei Zhou #  1 , Ruidong Li  1 , Yuping Yin  1 , Gengchen Xie  1 , Liang Shi  1 , Peng Zhang  2 , Kaixiong Tao  3
Affiliations

Investigating the role of itaconate in macrophage activation and oxidative stress injury in sepsis-associated acute kidney injury

Lei Yang et al. Mol Biol Rep. .

Abstract

Background: Sepsis may be linked to oxidative stress and can be controlled by itaconate, an activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Nevertheless, the itaconate impact on sepsis-associated acute kidney injury (SA-AKI) has yet to be definitively established.

Methods: We employed SA-AKI mouse model through a cecal ligation and puncture (CLP) procedure for the in vivo investigation of the potential nephroprotective effect of itaconate in this study. A plasmid was transfected into RAW264.7 cells to examine the Nrf2 pathway function after itaconate administration. Finally, the immune-responsive gene 1-knockout (IRG1-/-) mice were used to study the itaconate impacts on oxidative stress-induced SA-AKI.

Results: We have shown that 4-octyl itaconate (OI) significantly reduced CD11b-positive macrophage aggregation and activated the Nrf2 pathway in the bone marrow-derived macrophages (BMDM). The impacts of Nrf2 inhibitor ML385 on the anti-inflammatory and antioxidant properties of itaconate were found to be partial. OI inhibited lipopolysaccharide-induced oxidative stress injury in RAW264.7 macrophages and activated Nrf2 in the nucleus to hinder the expression of nuclear factor kappa B p65, thereby suppressing oxidative stress injury in the macrophages. Additionally, the introduction of the transfected plasmid resulted in a partial inhibition of the anti-inflammatory impact of itaconate. The kidney injury caused by sepsis exhibited greater severity in the IRG1-/- mice than in the wild type mice. Exogenous OI partially attenuated the kidney injury induced by sepsis in the IRG1-/- mice and suppressed the oxidative stress injury in macrophages.

Conclusions: This investigation offers new proof to support the itaconate function in the development and progression of SA-AKI and shows a new possible therapeutic agent for the SA-AKI treatment.

Keywords: Acute kidney injury; Itaconate; Nrf2; Oxidative stress; Sepsis.

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