Maresin conjugates in tissue regeneration-1 suppresses ferroptosis in septic acute kidney injury

Ji Xiao,Qian Yang,Linchao Li,Shengwei Jin,Ye’An Zhang,Yang Ye,Haoran Xu,Yi Yang

doi:10.1186/s13578-021-00734-x

Abstract

BackgroundFerroptosis is unique among different types of regulated cell death and closely related to organ injury. Whether ferroptosis occurs in sepsis-associated acute kidney injury (SA-AKI) is not clear. Nuclear factor-erythroid-2-related factor 2 (Nrf2) is crucial to the regulation of ferroptosis. We and others have shown that Maresin conjugates in tissue regeneration 1 (MCTR1) or other members of specialized pro-resolving mediators (SPMs) can actively regulate inflammation resolution and protect organs against injury in inflammatory diseases by activating the Nrf2 signaling. The aim of this study was to determine whether ferroptosis occurs in SA-AKI. Furthermore, we investigated the potential role and mechanism of MCTR1 in the regulation of ferroptosis in SA-AKI, which mainly focus on the Nrf2 signaling.ResultsWe demonstrated for the first time that ferroptosis is present in SA-AKI. Moreover, MCTR1 effectively suppressed ferroptosis in SA-AKI. Meanwhile, MCTR1 upregulated the expression of Nrf2 in the kidney of septic mice. Nrf2 inhibitor ML-385 reversed MCTR1-regulated ferroptosis and AKI, implying that Nrf2 is involved in the inhibitory effects of MCTR1 on ferroptosis in SA-AKI. Further, MCTR1 inhibited ferroptosis and elevated the expression of Nrf2 in LPS-induced HK-2 cells. However, Nrf2 siRNA offset the effect of MCTR1 on ferroptosis. Finally, we observed that MCTR1 ameliorates multi-organ injury and improves survival in animal models of sepsis.ConclusionsThese data demonstrate that MCTR1 suppresses ferroptosis in SA-AKI through the Nrf2 signaling. Our study enriches the pathophysiological mechanism of SA-AKI and provides new therapeutic ideas and potential intervention targets for SA-AKI.

Highlights

Sepsis has long been considered the chief cause of acute kidney injury (AKI) in intensive care unit [1]
Ferroptosis is present in CLP‐induced AKI We first examined the effect of caecal ligation and puncture (CLP) on acute kidney injury (AKI)
Transmission electron microscopy shown that the length of mitochondria in renal tubular epithelial cells (TECs) of the CLP group shortened at 12 h and significantly shorter at 24 h

Summary

Introduction

Sepsis has long been considered the chief cause of acute kidney injury (AKI) in intensive care unit [1]. Ferroptosis, a unique form of regulated cell death, was proposed by Stockwell et al in 2012 [12]. It is characterized by a lethal accumulation of iron-dependent lipid hydroperoxides. Studies have shown that ferroptosis is a primary contributor in models of organ injury, including degenerative brain disorders, ischemic injury to the heart, liver, intestine as well as other [15] Up to now, it is not clear whether ferroptosis exists in SA-AKI. Ferroptosis is unique among different types of regulated cell death and closely related to organ injury. Whether ferroptosis occurs in sepsis-associated acute kidney injury (SA-AKI) is not clear. We investigated the potential role and mechanism of MCTR1 in the regulation of ferroptosis in SA-AKI, which mainly focus on the Nrf signaling

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