XJB-5-131 inhibited ferroptosis in tubular epithelial cells after ischemia\u2212reperfusion injury

Zhi Zhao,Zhangyin Ming,Huzi Xu,Rui Zeng,Gang Xu,Ying Yao,Zhizhi Hu,Zhimei Ma,Cheng Zhou,Bicui Han,Han Zhu,Jianliang Wu

doi:10.1038/s41419-020-02871-6

Abstract

Regulated necrosis has been reported to exert an important role in the pathogenesis of various diseases, including renal ischemia-reperfusion (I/R) injury. Damage to renal tubular epithelial cells and subsequent cell death initiate the progression of acute kidney injury (AKI) and subsequent chronic kidney disease (CKD). We found that ferroptosis appeared in tubular epithelial cells (TECs) of various human kidney diseases and the upregulation of tubular proferroptotic gene ACSL4 was correlated with renal function in patients with acute kidney tubular injury. XJB-5-131, which showed high affinity for TECs, attenuated I/R-induced renal injury and inflammation in mice by specifically inhibiting ferroptosis rather than necroptosis and pyroptosis. Single-cell RNA sequencing (scRNA-seq) indicated that ferroptosis-related genes were mainly expressed in tubular epithelial cells after I/R injury, while few necroptosis- and pyroptosis-associated genes were identified to express in this cluster of cell. Taken together, ferroptosis plays an important role in renal tubular injury and the inhibition of ferroptosis by XJB-5-131 is a promising therapeutic strategy for protection against renal tubular cell injury in kidney diseases.

Highlights

Renal ischemia−reperfusion injury (I/R) often occurs following infection, trauma or surgery[1,2]
By using transmission electron microscopy, we observed the mitochondria damage in human tubular epithelial cells (TECs) with IgA nephropathy (IgAN), membranous glomerulonephritis (MN) and acute tubular injury (ATI)
In this study, we first confirmed ferroptosis in the human TECs with clinical kidney diseases by transmission electron microscopy and found the expression of the proferroptotic gene acyl-CoA synthetase longchain family member 4 (ACSL4) in tubular cells was correlated with severity of kidney function decline, and we identified that a potential ferroptosis inhibitor, XJB-5-131, which has a high affinity for the kidney, especially renal TECs, showed the potential to alleviate kidney injury, promote proliferation and repair of TECs, decrease kidney inflammation and inhibited the accumulation of lipid peroxidation but did not affect necroptosis and pyroptosis in I/R model

Summary

Introduction

Renal ischemia−reperfusion injury (I/R) often occurs following infection, trauma or surgery[1,2]. The pathophysiology of renal I/R injury is characterized by renal tubular damage, inflammation and vascular dysfunction, during which tubular cell death is considered the primary pathogenic event. Renal tubular epithelial cells (TECs) are the main cells in the kidney and are vulnerable to injuries, including toxins, hypoxia, mechanical injury and senescence. Accumulating evidence suggests that maladaptive repair of TECs has a Regulated necrosis, which is characterized by cell swelling and destruction of the integrity of the cellular membrane, has been considered to be the dominant contributor to acute tubular necrosis, including pyroptosis, necroptosis and ferroptosis. Pyroptosis is a programmed cell death that is characterized by the release of cellular contents and activation of a strong inflammatory response that relies on the enzymatic activity of inflammatory proteases with the regulation of caspases and gasdermin D (GSDMD)[7,8,9,10].

Methods

Results

Conclusion