Alternative polyadenylation trans-factor FIP1 exacerbates UUO/IRI-induced kidney injury and contributes to AKI-CKD transition via ROS-NLRP3 axis

Tong Zheng,Yuqin Tan,Jinhua Zhang,Jiang Qiu,Ning Na,Zhenwei Xie,Xiao Hu

doi:10.1038/s41419-021-03751-3

Abstract

NLRP3, a decisive role in inflammation regulation, is obviously upregulated by oxidative stress in kidney injury. The NLRP3 upregulation leads to unsolved inflammation and other pathological effects, contributing to aggravation of kidney injury and even transition to chronic kidney disease (CKD). However, the mechanism for NLRP3 upregulation and further aggravation of kidney injury remains largely elusive. In this study, we found NLRP3 3′UTR was shortened in response to kidney injury in vivo and oxidative stress in vitro. Functionally, such NLRP3 3′UTR shortening upregulated NLRP3 expression and amplified inflammation, fibrogenesis, ROS production and apoptosis, depending on stabilizing NLRP3 mRNA. Mechanistically, FIP1 was found to bind to pPAS of NLRP3 mRNA via its arginine-rich domain and to induce NLRP3 3′UTR shortening. In addition, FIP1 was upregulated in CKD specimens and negatively associated with renal function of CKD patients. More importantly, we found FIP1 was upregulated by oxidative stress and required for oxidative stress-induced NLRP3 upregulation, inflammation activation, cell damage and apoptosis. Finally, we proved that FIP1 silencing attenuated the inflammation activation, fibrogenesis, ROS production and apoptosis induced by UUO or IRI. Taken together, our results demonstrated that oxidative stress-upregulated FIP1 amplified inflammation, fibrogenesis, ROS production and apoptosis via inducing 3′UTR shortening of NLRP3, highlighting the importance of crosstalk between oxidative stress and alternative polyadenylation in AKI-CKD transition, as well as the therapeutic potential of FIP1 in kidney injury treatment.

Highlights

Acute and chronic kidney injury, generally caused by ischemia, obstructive pathologies and chemical drug, have become a major health concern worldwide with high mortality and morbidity[1]
Since aggravated kidney injury is very likely to turn into chronic kidney disease (CKD), we investigated the expression of FIP1 in clinical CKD specimens to determine whether FIP1 is a contributor of AKI-CKD transition
Since we found 3′ untranslated regions (3′UTR) shortening of NLRP3 was induced by oxidative stress and governed by APA trans-factor FIP1, we wondered whether oxidative stress functioned upstream of FIP1

Summary

Introduction

Acute and chronic kidney injury, generally caused by ischemia, obstructive pathologies and chemical drug, have become a major health concern worldwide with high mortality and morbidity[1]. The long-term ending of kidney injury is chronic kidney disease (CKD) and even kidney failure. There remain no effective drugs for kidney injury[2,3]. Oxidative stress and inflammation are the most significant characteristics, as well as pivotal pathological factors[4]. Inflammation initially emerges as a reno-protective role. Amplified inflammation, especially induced by oxidative stress, turns into pro-injury effects in multiple ways[5,6], making inhibition of amplified inflammation as a promising therapeutic strategy of kidney injury[7,8,9]

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Conclusion