BCL6 attenuates renal inflammation via negative regulation of NLRP3 transcription

Dan Chen,Yu-Ming Kang,Qi Chen,Ying Tong,Xiao-Qing Xiong,Ying-Hao Zang,Bing Zhou,Guo-Qing Zhu,Xing-Ya Gao,Yue-Hua Li

doi:10.1038/cddis.2017.567

Abstract

Renal inflammation contributes to the pathogeneses of hypertension. This study was designed to determine whether B-cell lymphoma 6 (BCL6) attenuates renal NLRP3 inflammasome activation and inflammation and its underlying mechanism. Male spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were used in the present study. Angiotensin (Ang) II or lipopolysaccharides (LPS) was used to induce inflammation in HK-2 cells, a human renal tubular epithelial (RTE) cell line. NLRP3 inflammasome was activated and BCL6 was downregulated in the kidneys of SHR. Either Ang II or LPS suppressed BCL6 expression in HK-2 cells. BCL6 overexpression in HK-2 cells attenuated Ang II-induced NLRP3 upregulation, inflammation and cell injury. The inhibitory effects of BCL6 overexpression on NLRP3 expression and inflammation were also observed in LPS-treated HK-2 cells. BCL6 inhibited the NLRP3 transcription via binding to the NLRP3 promoter. BCL6 knockdown with shRNA increased NLRP3 and mature IL-1β expression levels in both PBS- or Ang II-treated HK-2 cells but had no significant effects on ASC, pro-caspase-1 and pro-IL-1β expression levels. BCL6 overexpression caused by recombinant lentivirus expressing BCL6 reduced blood pressure in SHR. BCL6 overexpression prevented the upregulation of NLRP3 and mature IL-1β expression levels in the renal cortex of SHR. The results indicate that BCL6 attenuates Ang II- or LPS-induced inflammation in HK-2 cells via negative regulation of NLRP3 transcription. BCL6 overexpression in SHR reduced blood pressure, NLRP3 expression and inflammation in the renal cortex of SHR.

Highlights

Hypertension is recognized as a chronic, low-grade inflammatory disease in the kidneys and blood vessels.[1]
Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation is involved in several inflammatory diseases.[27,28]
The major novel findings in the present study are that B-cell lymphoma 6 (BCL6) binds to the promoter region of NLRP3 and negatively regulates NLRP3 expression, BCL6 overexpression inhibits Ang II- or LPS-induced NLRP3 upregulation and inflammation and BCL6 knockdown exacerbates Ang IIinduced NLRP3 upregulation and inflammation in HK-2 cells

Summary

Introduction

Hypertension is recognized as a chronic, low-grade inflammatory disease in the kidneys and blood vessels.[1]. Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is a multi-protein complex and is composed of NLRP3, apoptotic speck protein containing a caspase recruitment domain (ASC) and pro-caspase1.11 It can be triggered by exogenous and endogenous stimuli, including pathogen-associated molecular patterns and damage-associated molecular patterns, both of which belong to pattern-recognition receptors (PRRs).[12] Once stimulated, the NLRP3 inflammasome is assembled, and caspase-1 is activated, which processes pro-IL-1β into its mature form IL-1β, and triggers an inflammatory response.[11] Under both physiological and pathological conditions, PRRs are widely expressed in the kidney.[13,14] NLRP3 inflammasome promotes renal inflammation and contributes to chronic kidney disease (CKD).[13] NLRP3 deficiency ameliorated fructoseinduced renal injury by reducing renal inflammation, fibrosis, albuminuria and hyperuricemia.[15] Knockdown of LincRNAGm4419 attenuates NLRP3 inflammasome-mediated inflammation in diabetic nephropathy.[16]. The present study was designed to determine whether BCL6 attenuates renal NLRP3 inflammasome activation and inflammation and its underlying mechanism

Methods

Results

Conclusion