Huiling Xiang

Inflammasomes, multiprotein complex induced by harmful factors in the body, play a crucial role in innate immunity. Activation of inflammasomes lead to the activation of casepase-1 and then the secretion of inflammatory cytokines, including IL-1β and IL-18, subsequently leading to a type of cell death called pyroptosis. There are two types of signaling pathways involved in the process of inflammasome activation: the canonical and the non-canonical signaling pathway. The canonical signaling pathway is mainly dependent on casepase-1; the non-canonical signal pathway, which was recently discovered, is mainly dependent on caspase-11, but is also meditated by caspase-4, caspase-5, and caspase-8. Kidney inflammation is basically associated with inflammatory factor exudation and inflammatory cell infiltration. Several studies have showed that inflammasomes are closely related to kidney diseases, especially the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome, which play a role in regulating kidney inflammation and fibrosis. In this review, we focus on the relationship between inflammasomes and kidney diseases, especially the role of the NLRP3 inflammasome in different kinds of kidney disease via both canonical and non-canonical signal pathways.

BACKGROUND: Sepsis-associated AKI has been shown to be related to sepsis mortality. Macrophage activation and endothelial cell damage are involved in the progression of sepsis-associated AKI, but the specific mechanisms are still unclear. METHODS: In vitro experiments, exosomes extracted from lipopolysaccharide (LPS) -stimulated macrophages were co-incubated with rat glomerular endothelial cells (RGECs) and then detected the injury markers of RGECs. Acid sphingomyelinase (ASM) inhibitor amitriptyline were used to investigate the role of ASM. In vivo experiment, exosomes produced by LPS-stimulated macrophages were injected into mice through tail vein to further explore the role of macrophage-derived exosomes. Moreover, ASM knockout mice were used to verify the mechanism. RESULT: In vitro, the secretion of macrophage exosomes increased upon the stimulation with LPS. Notably, macrophage-derived exosomes can cause glomerular endothelial cell dysfunction. In vivo, macrophage infiltration and exosome secretion in glomeruli of the LPS-induced AKI group increased. The exosomes produced by LPS-stimulated macrophages were injected into mice, which also led to the injury of renal endothelial cells. In addition, in the LPS-induced AKI mouse model, compared with wild-type mice, the secretion of exosomes in glomeruli of ASM gene knockout mice and the injury of endothelial cells were reduced. CONCLUSION: Our study shows that ASM regulates the secretion of macrophage exosomes, leading to endothelial cell injury, which may be a therapeutic target in sepsis-associated AKI.

<b><i>Background:</i></b> Membranous nephropathy (MN), a major cause of nephrotic syndrome, has attracted people’s attention in recent years for its growing prevalence. It is the second or third leading cause of ESRD in patients with primary glomerulonephritis and is the leading glomerulopathy that recurs after kidney transplantation. <b><i>Summary:</i></b> MN can be classified as idiopathic membranous nephropathy (IMN) and secondary MN. The discovery of the M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) provides the new diagnostic methods and treatment strategies for IMN on the molecular level. The study on single nucleotide polymorphism of IMN genes, such as the single M-type phospholipase A2 receptor 1 (<i>PLA2R1</i>) gene and human leukocyte antigen (<i>HLA</i>) gene, explains the pathogenesis of the disease from the perspective of genetics and conforms to the trend of the era of precision medicine. <b><i>Key Messages:</i></b> This review focuses on advances in the pathogenesis of IMN, including molecular and genetic pathogenesis, as well as discussing the diagnostic and treatment guiding value brought by these new discoveries.

AIM: Coronavirus disease 2019 (COVID-19) has been associated with increased mortality and morbidity from thromboembolism, especially venous thromboembolism. There are more limited data for systemic thromboembolism. The present study aimed to investigate the prevalence of systemic and venous thromboembolism as well as major bleeding and mortality in relation to underlying risk factors and the impact of anticoagulation use in hospitalized patients with COVID-19. METHODS AND RESULTS: Patients with COVID-19 admitted to Union Hospital, Wuhan, Hubei, China between January 08, 2020 and April 7, 2020 were enrolled in this retrospective study. Cox proportional hazard models were utilized to determine associated risk factors for clinical events, adjusting for the severity of COVID-19 infection, drug therapies, comorbidities, surgery, and use of antithrombotic drugs. There were 1125 patients (49.9% male; mean age 58 years (standard deviation, SD, 15 years)) with a mean follow-up of 21 (SD 13) days. Approximately 25 (30%) patients with thromboembolism also suffered bleeding events. Age was an independent risk factor for thromboembolism, bleeding events, and death (all p<0.05). After adjusting for the severity of COVID-19 infection, comorbidities, surgery, antiviral drugs, immunomodulators, Chinese herbs, and antithrombotic drugs, low lymphocyte counts (hazard ratio, HR, 95% confidence interval (CI), 1.03, 1.01-1.05, p=0.01) and surgery (HR 2.80, 1.08-7.29, p=0.03) independently predicted the risk for major bleeding, whereas liver dysfunction (HR 4.13, 1.30-13.1, p=0.02) was an independent risk factor for patients with both thromboembolism and bleeding events. CONCLUSIONS: Patients with COVID-19 were at high risk for thromboembolic and bleeding events as well as mortality. The use of anticoagulants, especially parenteral anticoagulants, significantly reduced the risk for composite outcomes of thromboembolism, bleeding events, and death. The presence of AF was a contributor to systemic thromboembolism in COVID-19 patients.