NLRP3 associated with chronic kidney disease progression after ischemia/reperfusion-induced acute kidney injury

Zhihuang Zheng,Zhonghua Zhao,Jinfang Bao,Jun Liu,Yili Fang,Nan Zhu,Chenyang Qi,Kexin Xu,Huijuan Wu,Qing Yu,Chuanlei Li

doi:10.1038/s41420-021-00719-2

Abstract

Nod-like receptor protein 3 (NLRP3), as an inflammatory regulator, has been implicated in acute kidney injury (AKI). Failed recovery after AKI can lead to chronic kidney disease (CKD). However, the role of NLRP3 in the AKI-CKD transition is still unknown. A mild or severe AKI mouse model was performed by using ischemia-reperfusion injury (IRI). We evaluated the renal NLRP3 expression in acute and chronic phases of ischemic AKI, respectively. Although serum creatinine (Cr) and blood urea nitrogen (BUN) levels in AKI chronic phase were equivalent to normal baseline, histological analysis and fibrotic markers revealed that severe AKI-induced maladaptive tubular repair with immune cell infiltration and fibrosis. Tubular damage was restored completely in mild AKI rather than in severe AKI. Of note, persistent overexpression of NLRP3 was also found in severe AKI but not in mild AKI. In the severe AKI-induced chronic phase, there was a long-term high level of NLRP3 in serum or urine. Overt NLRP3 was mainly distributed in the abnormal tubules surrounded by inflammatory infiltrates and fibrosis, which indicated the maladaptive repair. Renal Nlrp3 overexpression was correlated with infiltrating macrophages and fibrosis. Renal NLRP3 signaling-associated genes were upregulated after severe AKI by RNA-sequencing. Furthermore, NLRP3 was found increased in renal tubular epitheliums from CKD biopsies. Together, persistent NLRP3 overexpression was associated with chronic pathological changes following AKI, which might be a new biomarker for evaluating the possibility of AKI-CKD transition.

Highlights

Acute kidney injury (AKI) is an increasingly common complication occurring in critically ill patients with high morbidity and mortality [1, 2]
Short- and long-term outcomes were evaluated in 2 and 28 days after surgery. b Serum creatinine and c blood urine nitrogen levels of two group mice subjected to mild and severe renal Ischemia-reperfusion injury (IRI) at indicated time points. n = 5 for mild AKI and severe AKI mice, respectively. d Representative images of the renal cortex 2 days after surgery stained with hematoxylin and eosin (HE). e Semi-quantitative scoring of renal tubular damage in kidneys at 48 h after surgery considering tubular dilation, brush border loss, tubular degeneration, tubular cast formation, and tubular necrosis. f Representative images of the renal cortex 28 days after surgery stained with HE
Nod-like receptor protein 3 (NLRP3) overexpression was associated with maladaptive tubular repair and correlated with inflammatory infiltration and fibrosis To examine whether renal increased NLRP3 has a link to renal failed recovery, we examined the expressed location of NLRP3, as well as renal inflammatory infiltration and interstitial fibrosis by the 28th day after surgery

Summary

Introduction

Acute kidney injury (AKI) is an increasingly common complication occurring in critically ill patients with high morbidity and mortality [1, 2]. Previous clinical studies demonstrate that AKI predisposes to the development and progression of chronic kidney disease (CKD), and the concept of AKI-CKD transition has been established [3,4,5,6]. Ischemia-reperfusion injury (IRI) is a common cause of clinically severe AKI [7,8,9]. How to early identify progressive AKI with tubular maladaptive repair is poorly understood. New noninvasive biomarkers are urgently needed to identify patients whether are at high risk for AKI-CKD transition or not

Methods

Results

Conclusion