ChREBP Deficiency Suppresses Renal Inflammation and Fibrosis Via Inhibiting NLRP3 Inflammasome Activation in Diabetic Kidney Disease.

IF 2.1 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL
Discovery medicine Pub Date : 2022-03-01
Nan Chen, Zhifen Yang, Lin Mu, Ming Wu, Jing Song, Tengxiao Zhou, Yonghong Shi
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引用次数: 0

Abstract

Background and aim: Diabetic kidney disease (DKD) is the most-common cause of chronic renal failure and end-stage renal disease (ERSD) in diabetes mellitus (DM) patients. Renal inflammation and glomerular or interstitial fibrosis are mainly associated with the progression of DKD. Carbohydrate response element binding protein (ChREBP) is activated and transcribed in a glucose dependent manner. This study is aimed at exploring the role and underlying mechanisms of ChREBP in DKD.

Methods: ChREBP knockout mice, obtained by CRISPR Cas9 gene editing technology, were used to study the effects of ChREBP on inflammation and fibrosis in diabetic kidney of mice. Human renal tubular epithelial (HK-2) cells were cultured in a medium containing normal or high glucose levels. Additionally, the role of ChREBP in high glucose (HG)-induced NLRP3 inflammasome activation was assessed.

Results: We identified that renal inflammation, renal extracellular matrix deposition, and renal fibrosis were restored by ChREBP deficiency in diabetic mouse kidney. Consequently, ChREBP deficiency decreased the activation of nucleotide leukin-rich polypeptide 3 (NLRP3) inflammasome, which later restrained hyperglycemia-induced renal fibrosis. Importantly, NLRP3 inflammasome aggravated the above-mentioned renal fibrosis via TGF-β1 expression and the signaling pathways of Smad2/3 and the p38 MAPK. Additionally, ChREBP deficiency inhibited NLRP3 inflammasome activation both in HG-induced HK-2 cells and diabetic mouse kidney.

Conclusion: Our findings establish a critical role of ChREBP in engaging inflammation and renal fibrosis by regulating NLRP3 inflammasome activation in DKD.

ChREBP缺乏通过抑制NLRP3炎性体激活抑制糖尿病肾病的肾脏炎症和纤维化
背景与目的:糖尿病肾病(DKD)是糖尿病(DM)患者慢性肾功能衰竭和终末期肾病(ERSD)最常见的病因。肾脏炎症和肾小球或间质纤维化主要与DKD进展相关。碳水化合物反应元件结合蛋白(ChREBP)以葡萄糖依赖的方式被激活和转录。本研究旨在探讨ChREBP在DKD中的作用及其潜在机制。方法:利用CRISPR Cas9基因编辑技术获得ChREBP敲除小鼠,研究ChREBP对糖尿病小鼠肾脏炎症和纤维化的影响。人肾小管上皮细胞(HK-2)在含有正常或高葡萄糖水平的培养基中培养。此外,我们还评估了ChREBP在高糖(HG)诱导的NLRP3炎性体激活中的作用。结果:我们发现ChREBP缺乏可恢复糖尿病小鼠肾脏炎症、肾细胞外基质沉积和肾纤维化。因此,ChREBP缺乏降低了富含核苷酸白素多肽3 (NLRP3)炎症小体的激活,这后来抑制了高血糖诱导的肾纤维化。重要的是,NLRP3炎性体通过TGF-β1的表达以及Smad2/3和p38 MAPK的信号通路加重了上述肾纤维化。此外,ChREBP缺乏抑制hg诱导的HK-2细胞和糖尿病小鼠肾脏中NLRP3炎性体的激活。结论:我们的研究结果表明,ChREBP通过调节NLRP3炎症小体的激活,在DKD中参与炎症和肾纤维化的关键作用。
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来源期刊
Discovery medicine
Discovery medicine MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
5.40
自引率
0.00%
发文量
80
审稿时长
6-12 weeks
期刊介绍: Discovery Medicine publishes novel, provocative ideas and research findings that challenge conventional notions about disease mechanisms, diagnosis, treatment, or any of the life sciences subjects. It publishes cutting-edge, reliable, and authoritative information in all branches of life sciences but primarily in the following areas: Novel therapies and diagnostics (approved or experimental); innovative ideas, research technologies, and translational research that will give rise to the next generation of new drugs and therapies; breakthrough understanding of mechanism of disease, biology, and physiology; and commercialization of biomedical discoveries pertaining to the development of new drugs, therapies, medical devices, and research technology.
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