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Inflammasome and the kidneys

Takuya Wakamatsu, Suguru Yamamoto, Toru Ito, Yoko Sato, Koji Matsuo, Yoshimitsu Takahashi, Yoshikatsu Kaneko, Shin Goto, Junichiro James Kazama, Fumitake Gejyo, Ichiei Narita
In chronic kidney disease (CKD) patients, accumulation of uremic toxins is associated with cardiovascular risk and mortality. One of the hallmarks of kidney disease-related cardiovascular disease is intravascular macrophage inflammation, but the mechanism of the reaction with these toxins is not completely understood. Macrophages differentiated from THP-1 cells were exposed to indoxyl sulfate (IS), a representative uremic toxin, and changes in inflammatory cytokine production and intracellular signaling molecules including interleukin (IL)-1, aryl hydrocarbon receptor (AhR), nuclear factor (NF)-κ, and mitogen-activated protein kinase (MAPK) cascades as well as the NLRP3 inflammasome were quantified by real-time PCR, Western blot analysis, and enzyme-linked immunosorbent assay...
March 15, 2018: Toxins
Nilubon Singhto, Rattiyaporn Kanlaya, Angkhana Nilnumkhum, Visith Thongboonkerd
In kidney stone disease, macrophages secrete various mediators via classical secretory pathway and cause renal interstitial inflammation. However, whether their extracellular vesicles, particularly exosomes, are involved in kidney stone pathogenesis remained unknown. This study investigated alterations in exosomal proteome of U937-derived macrophages (by phorbol-12-myristate-13-acetate activation) after exposure to calcium oxalate monohydrate (COM) crystals for 16-h using 2-DE-based proteomics approach. Six significantly altered proteins in COM-treated exosomes were successfully identified by nanoscale liquid chromatography-electrospray ionization-electron transfer dissociation tandem mass spectrometry as proteins involved mainly in immune processes, including T-cell activation and homeostasis, Fcγ receptor-mediated phagocytosis, interferon-γ (IFN-γ) regulation, and cell migration/movement...
2018: Frontiers in Immunology
Tao Ding, Shaofei Wang, Xuyao Zhang, Wenjing Zai, Jiajun Fan, Wei Chen, Qi Bian, Jingyun Luan, Yilan Shen, Yanda Zhang, Dianwen Ju, Xiaobin Mei
BACKGROUND: Diabetic nephropathy (DN), the leading cause of end-stage renal disease, is acknowledged as an independent risk factor for cardiovascular disease, which underlines the urgent need for new medications to DN. Dihydroquercetin (DHQ), an important natural dihydroflavone, exerts significant antioxidant, anti-inflammatory, and antifibrotic properties, but its effects on DN have not been investigated yet. PURPOSE: We aimed to explore the kidney protection effects of DHQ on DN rats induced by high-fat diet/streptozotocin in vivo and the underlying mechanisms of DHQ on renal cells including HBZY-1 and HK2 exposed to high glucose in vitro...
March 1, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Kang Wang, Lei Hu, Jian-Kang Chen
Recent preclinical and clinical evidence suggests that hyperuricemia (HU) is an independent risk factor for metabolic syndrome, hypertension, cardiovascular disease and chronic kidney disease. Receptor-interacting protein 3 (RIP3) is an important contributor in inducing programmed necrosis, representing a newly identified mechanism of cell death combining features of both apoptosis and necrosis. In our study, RIP3 was strongly expressed in mice with hyperuricemia. RIP3 deficiency attenuated hyperuricemia in mice, evidenced by reduced serum uric acid and creatinine and enhanced urinary uric acid and creatinine, as well as the improved histological alterations in renal sections...
March 5, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Lotte Kors, Elena Rampanelli, Geurt Stokman, Loes Butter, Ntsiki M Held, Nike Claessen, Per W B Larsen, Joanne Verheij, Coert J Zuurbier, Gerhard Liebisch, Gerd Schmitz, Stephen E Girardin, Sandrine Florquin, Riekelt H Houtkooper, Jaklien C Leemans
NOD-like receptor (NLR)X1 (NLRX1) is an ubiquitously expressed inflammasome-independent NLR that is uniquely localized in mitochondria with as yet unknown effects on metabolic diseases. Here, we report that NLRX1 is essential in regulating cellular metabolism in non-immune parenchymal hepatocytes by decreasing mitochondrial fatty acid-dependent oxidative phosphorylation (OXPHOS) and promoting glycolysis. NLRX1 loss in mice has a profound impact on the prevention of diet-induced metabolic syndrome parameters, non-alcoholic fatty liver disease (NAFLD) progression, and renal dysfunction...
March 4, 2018: Biochimica et Biophysica Acta
Yong-Huai Li, Xiang Wei, Shuang Ji, Shu-Yu Gui, Su-Mei Zhang
The present study aimed to investigate the effects of nucleotide-binding domain leucine-rich repeat protein (NLRP)1/NLRP3 inflammasome pathways on latent viral infection of the respiratory tract. A total of 55 BALB/c mice were assigned to the control, bleomycin (BLM)‑treated, murine cytomegalovirus (MCMV), MCMV+BLM and MCMV+BLM+CD4+ T‑cell groups. The viral loads were detected in the salivary glands, kidney, liver and lung tissues via polymerase chain reaction (PCR). The weight, lung coefficient and hydroxyproline (HYP) were detected...
February 28, 2018: International Journal of Molecular Medicine
Orestes Foresto-Neto, Victor Ferreira Ávila, Simone Costa Alarcon Arias, Fernanda Florencia Fregnan Zambom, Lisienny Campoli Tono Rempel, Viviane Dias Faustino, Flavia Gomes Machado, Denise Maria Avancini Costa Malheiros, Hugo Abensur, Niels Olsen Saraiva Camara, Roberto Zatz, Clarice Kazue Fujihara
Recent studies suggest that NLRP3 inflammasome activation is involved in the pathogenesis of chronic kidney disease (CKD). Allopurinol (ALLO) inhibits xanthine oxidase (XOD) activity, and, consequently, reduces the production of uric acid (UA) and reactive oxygen species (ROS), both of which can activate the NLRP3 pathway. Thus, ALLO can contribute to slow the progression of CKD. We investigated whether inhibition of XOD by ALLO reduces NLRP3 activation and renal injury in the 5/6 renal ablation (Nx) model...
March 6, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
Yochai Birnbaum, Mandeep Bajaj, Hsiu-Chiung Yang, Yumei Ye
BACGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 inhibitors (DPP4I) are used to treat type 2 diabetes (T2DM). DPP4 inhibitors (DPP4) attenuate Nlrp3 inflammasome activation in the kidney. SGLT2 inhibition reduces inflammation and attenuates the progression of diabetic nephropathy (DN). The effects of dapagliflozin (Dapa) on the activation of the Nlrp3 inflammasome and the combined effect of SGLT2 and DPP4 on T2DM-induced inflammasome activation and progression of DN have not been previously studied...
March 5, 2018: Cardiovascular Drugs and Therapy
Tao-Tao Tang, Lin-Li Lv, Ming-Ming Pan, Yi Wen, Bin Wang, Zuo-Lin Li, Min Wu, Feng-Mei Wang, Steve D Crowley, Bi-Cheng Liu
Inflammation is a major contributor to the pathogenesis of ischemic acute kidney injury (AKI), which complicates the post-operative outcomes of large numbers of hospitalized surgical patients. Hydroxychloroquine (HCQ), a well-known anti-malarial drug, is commonly used in clinical practice for its anti-inflammatory actions. However, little is known about its role in renal ischemia/reperfusion (I/R) injury. In the current study, mice were subjected to I/R injury and HCQ was administered for seven days by gavage prior to surgery...
March 2, 2018: Cell Death & Disease
Li-Rong Lin, Yao Xiao, Wei Liu, Yu-Yan Chen, Xiao-Zhen Zhu, Zheng-Xiang Gao, Kun Gao, Man-Li Tong, Hui-Lin Zhang, Shu-Lian Li, Hui-Ling Lin, Wen-Dong Li, Xian-Ming Liang, Yong Lin, Li-Li Liu, Tian-Ci Yang
BACKGROUND: The inflammasome responses in Treponema pallidum infection have been poorly understood to date. This study aimed to investigate the expression of the nucleotide-binding leucine-rich receptor protein 3 (NLRP3) inflammasome in the development of tissue inflammation in rabbits infected with T. pallidum. METHODS: Forty-five rabbits were randomly assigned to a blank group or an infection group, and the latter was divided into no benzathine penicillin G (BPG) and BPG treatment subgroups...
March 1, 2018: BMC Infectious Diseases
Nishkantha Arulkumaran, Marije L Sixma, Sean Pollen, Elias Ceravola, Elisa Jentho, Maria Prendecki, Paul S Bass, Frederick W K Tam, Robert J Unwin, Mervyn Singer
Sepsis is a major clinical problem associated with significant organ dysfunction and high mortality. The ATP-sensitive P2X7 receptor activates the NLRP3 inflammasome and is a key component of the innate immune system. We used a fluid-resuscitated rat model of fecal peritonitis and acute kidney injury (AKI) to investigate the contribution of this purinergic receptor to renal dysfunction in sepsis. Six and 24 h time-points were chosen to represent early and established sepsis, respectively. A selective P2X7 receptor antagonist (A-438079) dissolved in dimethyl sulfoxide (DMSO) was infused 2 h following induction of sepsis...
March 2018: Physiological Reports
Yi Wen, Yi-Ran Liu, Tao-Tao Tang, Ming-Ming Pan, Sheng-Chun Xu, Kun-Ling Ma, Lin-Li Lv, Hong Liu, Bi-Cheng Liu
Ischemia/reperfusion (I/R) is a critical risk factor for acute kidney injury (AKI). Recent studies provided evidence that tubular epithelial cells (TEC)-associated inflammation aggravates kidney injury and impairs tissue repair after I/R injury. Here we demonstrated that the Nod-like receptor protein 3 (NLRP3) inflammasome is activated by mitochondrial reactive oxygen species (mROS) during I/R injury via direct interactions between the inflammasome and thioredoxin-interacting protein (TXNIP). Firstly, we found that NLRP3 inflammasome activation was induced by I/R injury, peaking at day 3 after reperfusion...
February 22, 2018: International Journal of Biochemistry & Cell Biology
Yachun Han, Xiaoxuan Xu, Chengyuan Tang, Peng Gao, Xianghui Chen, Xiaofen Xiong, Ming Yang, Shikun Yang, Xuejing Zhu, Shuguang Yuan, Fuyou Liu, Li Xiao, Yashpal S Kanwar, Lin Sun
NLRP3/IL-1β activation via thioredoxin (TRX)/thioredoxin-interacting protein (TXNIP) following mitochondria ROS (mtROS) overproduction plays a key role in inflammation. However, the involvement of this process in tubular damage in the kidneys of patients with diabetic nephropathy (DN) is unclear. Here, we demonstrated that mtROS overproduction is accompanied by decreases in TRX expression and TXNIP up-regulation. In addition, we discovered that mtROS overproduction is also associated with increases in NLRP3/IL-1β and TGF-β expression in the kidneys of patients with DN and db/db mice...
February 15, 2018: Redox Biology
Junli Yan, Yao Li, Haiping Yang, Li Zhang, Baohui Yang, Mo Wang, Qiu Li
Studies show that the Th17/IL-17A axis plays an important role in the pathogenesis of kidney diseases. Previously, we also showed that IL-17A may play a role in the pathogenesis of primary nephrotic syndrome; however, the underlying mechanism(s) is unclear. The aim of this study was to explore the molecular mechanism of IL-17A inducing podocyte injury in vitro. In this study, the NLRP3 inflammsome activation and the morphology of podocytes were detected by western blot and immunofluorescence .The results showed that podocytes persistently expressed IL-17A receptor, and that NLRP3 inflammasome in these cells was activated upon exposure to IL-17A...
February 15, 2018: Scandinavian Journal of Immunology
Mo Chen, Xiaoyong Lu, Ci Lu, Ning Shen, Yujie Jiang, Menglu Chen, Huaxiang Wu
BACKGROUND: In addition to the kidney, the intestine is one of the most important organs involved in uric acid excretion. However, the mechanism of urate excretion in the intestine remains unclear. Therefore, the relationship between soluble uric acid and the gut excretion in human intestinal cells was explored. The relevant signaling molecules were then also examined. METHODS: HT-29 and Caco-2 cell lines were stimulated with soluble uric acid. Western blotting and qRT-PCR were used to measure protein and mRNA levels...
February 7, 2018: Arthritis Research & Therapy
Jeffrey B Kopp, Hila Roshanravan, Koji Okamoto
PURPOSE OF REVIEW: To review publications relating to apolipoprotein L1 (APOL1) renal risk variants published 2017. RECENT FINDINGS: The study of APOL1 variants continues to be highly active; 24 articles published in 2017 were selected to highlight. These include clinical studies of kidney disease, kidney transplantation, hypertension, cardiovascular disease, and genetic diversity. Laboratory studies included APOL1 association with vesicle-associated membrane soluble N-ethylmaleimide-sensitive factor activating protein receptor protein and with soluble urokinase-type plasminogen activator receptor, mitochondrial dysfunction, endolysosomal dysfunction, and inflammasome activation...
January 30, 2018: Current Opinion in Nephrology and Hypertension
Li-Han Chin, Yu-Juei Hsu, Shih-Che Hsu, Yen-Hui Chen, Yung-Lung Chang, Shih-Ming Huang, Chien-Sung Tsai, Chih-Yuan Lin
Chronic inflammation plays a crucial role in the long-term complications in patients with chronic kidney disease (CKD). This study aimed to assess the role of NLR pyrin domain-containing protein (NLRP3) inflammasome in cardiac contractile dysfunctions in CKD. The cardiac contractile function was evaluated and the expression of NLRP3 inflammasome and related cytokines in the heart was assessed in a murine sham-operated and 5/6 nephrectomy CKD model in vivo. In vitro, H9c2 cells were treated with uremic toxin indoxyl sulfate (IS), with or without NLRP3 inflammasome inhibition, which was achieved by using small interfering RNA (siRNA)-mediated knockdown of the NLRP3 gene...
December 26, 2017: Oncotarget
Maysa Sarhan, Anne von Mässenhausen, Christian Hugo, Rainer Oberbauer, Andreas Linkermann
Death of renal cells is central to the pathophysiology of acute tubular necrosis, autoimmunity, necrotizing glomerulonephritis, cystic kidney disease, urosepsis, delayed graft function and transplant rejection. By means of regulated necrosis, immunogenic damage-associated molecular patterns (DAMPs) and highly reactive organelles such as lysosomes, peroxisomes and mitochondria are released from the dying cells, thereby causing an overwhelming immunologic response. The rupture of the plasma membrane exhibits the "point of no return" for the immunogenicity of regulated cell death, explaining why apoptosis, a highly organized cell death subroutine with long-lasting plasma membrane integrity, elicits hardly any immune response...
January 25, 2018: Cell Death & Disease
Rui Wu, Xuanchen Liu, Jianyong Yin, Huijuan Wu, Xiulei Cai, Niansong Wang, Youcun Qian, Feng Wang
BACKGROUND AND OBJECTIVE: Interleukin 6 (IL-6) has been identified as a key mediator in inflammation, immune responses and glucose metabolism. In this study, we assessed the effects of an IL-6 receptor antibody on diabetic nephropathy in a mouse model of type 2 diabetes mellitus. METHODS: Twelve week old male db/db mice were treated with Tocilizumab (an IL-6 receptor antibody), normal IgG1 control antibody, insulin or normal saline for 12 weeks. Renal injury, inflammation and insulin resistance were assessed...
January 11, 2018: Metabolism: Clinical and Experimental
Wenbiao Wang, Geng Li, De Wu, Zhen Luo, Pan Pan, Mingfu Tian, Yingchong Wang, Feng Xiao, Aixin Li, Kailang Wu, Xiaohong Liu, Lang Rao, Fang Liu, Yingle Liu, Jianguo Wu
Zika virus (ZIKV) infection is a public health emergency and host innate immunity is essential for the control of virus infection. The NLRP3 inflammasome plays a key role in host innate immune responses by activating caspase-1 to facilitate interleukin-1β (IL-1β) secretion. Here we report that ZIKV stimulates IL-1β secretion in infected patients, human PBMCs and macrophages, mice, and mice BMDCs. The knockdown of NLRP3 in cells and knockout of NLRP3 in mice inhibit ZIKV-mediated IL-1β secretion, indicating an essential role for NLRP3 in ZIKV-induced IL-1β activation...
January 9, 2018: Nature Communications
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