Excessive Oxidative Stress Contributes to Increased Acute ER Stress Kidney Injury in Aged Mice.

Xiaoyan Liu,Youfei Guan,Zihan Zheng,Feng Zheng,Xiaoyan Zhang,Ruihua Zhang,Gary Striker,Helen Vlassara,Lianghu Huang

doi:10.1155/2019/2746521

Abstract

The aged kidney is susceptible to acute injury due presumably to its decreased ability to handle additional challenges, such as endoplasmic reticulum (ER) stress. This was tested by giving tunicamycin, an ER stress inducer, to either old or young mice. Injection of high dose caused renal failure in old mice, not in young mice. Moreover, injection of low dose resulted in severe renal damage in old mice, confirming the increased susceptibility of aged kidney to ER stress. There existed an abnormality in ER stress response kinetics in aged kidney, characterized by a loss of XBP-1 splicing and decreased PERK-eIF2α phosphorylation at late time point. The presence of excessive oxidative stress in aged kidney may play a role since high levels of oxidation increased ER stress-induced cell death and decreased IRE1 levels and XBP-1 splicing. Importantly, treatment with antioxidants protected old mice from kidney injury and normalized IRE1 and XBP-1 responses. Furthermore, older mice (6 months old) transgenic with antioxidative stress AGER1 were protected from ER stress-induced kidney injury. In conclusion, the decreased ability to handle ER stress, partly due to the presence of excessive oxidative stress, may contribute to increased susceptibility of the aging kidney to acute injury.

Highlights

Older individuals are more susceptible to renal failure caused by drug toxicity and ischemic injury [1, 2]
Since Endoplasmic reticulum (ER) stress is commonly associated with acute kidney injury caused by infection, drug toxicity, and ischemia [16, 18, 19, 32, 44], the inability to handle ER stress may be another mechanism for increased susceptibility to and severity of acute injury in aging kidney
We found a dysregulated unfolded protein response (UPR) dynamic in old mice: while UPR at 24 hours after high dose of tunicamycin treatment was similar between the kidneys of old and young mice, X-box binding protein 1 (XBP-1) splicing was lost at 48 hours and phosphorylated pancreatic ER kinase (PERK) and eIF2α were not elevated at 72 hours in old mice

Summary

Introduction

Older individuals are more susceptible to renal failure caused by drug toxicity and ischemic injury [1, 2]. Three separate pathways have been identified that regulate the UPR, including pancreatic ER kinase (PERK), activating transcription factor 6 (ATF6), and the inositol requiring enzyme 1 (IRE1) and X-box binding protein 1 (XBP-1) pathways [10,11,12]. These three pathways are activated in an attempt to reduce the stress. Increased acute stress has been shown to contribute to various diseases including diabetes mellitus, neurodegenerative diseases, cardiac disease, and atherosclerosis [9, 13, 14]

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Conclusion