Mechanism of NLRP3 inflammasome activation caused by albumin in renal tubulointerstitial cells / 临床与实验病理学杂志

Purpose To study the mechanism of NLRP3 inflammasome activation caused by albumin in renal tubulointerstitial cells.Methods Cathepsin B was detected by immunohistochemistry in renal biopsy tissue of 30 membranous nephropathy patients which had different levels of proteinuria.HK-2 cells were stimulated by albumin,and then were treated by high concentration KCl,CA 074 Me and DPI,which was Cathepsin B inhibitor and ROS inhibitor.Finally,IL-1β and IL-18 were detected by Western blot and real time PCR,respectively.Results The expression of Cathepsin B in tubulointerstitial cells was significantly higher in patients with severe proteinuria than that in patients with mild proteinuria (P ＜ 0.05).CA 074 Me and DPI significantly reduced IL-1β and IL-18 secretion in HK-2 cells stimulated by albumin (P ＜ 0.05),but high concentration KCl did not result in this change (P ＞ 0.05).Conclusion NLRP3 inflammasome is activated via Cathepsin B release and increases ROS production caused by proteinuria,but not via K + efflux.

Inflammation accelerates lipid dysregulation mediated cardiac fibrosis through enhancing myocardial endothelial-to-mesenchymal transition / 中华心血管病杂志

<p><b>OBJECTIVE</b>Dyslipidemia and chronic inflammation are risk factors of cardiac fibrosis. This study was aimed to investigate their possible synergetic effects and underlying mechanisms on progression of cardiac fibrosis in apolipoprotein E knockout (ApoE -/-) mice.</p><p><b>METHODS</b>Twenty-four ApoE-/- mice were divided into normal chow diet (control), high fat diet (HFD group), and HFD plus subcutaneously injection of 10% casein (inflammation group) for 8 weeks. Lipid profile and serum amyloid A (SAA) were examined by clinical biochemical assays and Enzyme-Linked Immunosorbent Assay, respectively. Hematoxylin-eosin staining (HE) and Masson staining were used to evaluate the myocardial accumulation of lipid and collagen. Collagen I protein expression was detected by immunohistochemical staining. Endothelial-to-mesenchymal transition related protein expressions were determined by Western blot.</p><p><b>RESULTS</b>Serum SAA level was significantly higher in inflammation group [(127.42 ± 26.99) ng/ml] than in control [(15.40 ± 7.62) ng/ml] and HFD [(8.17 ± 0.72) ng/ml] group (all P < 0.01).However serum levels of triglyceride, total cholesterol, and low density lipoprotein (LDL) cholesterol were significantly higher in HFD group than in inflammation and control groups[TG (7.53 ± 2.05) mmol/L vs. (3.43 ± 0.79) mmol/L; TC (27.80 ± 3.99) mmol/L vs. (14.94 ± 1.92) mmol/L;LDL-C (11.56 ± 2.56) mmol/L vs. (9.46 ± 1.31) mmol/L, all P < 0.05) . Foam cell formation in cardiac vessels, myocardial collagen deposit, protein expressions of collagen I, CD31, and alpha-smooth muscle actin (α-SMA) were all significantly higher in inflammation group than in HFD group (all P < 0.05) suggesting that inflammation contributes to the phenotype endothelial-to-mesenchymal transition in heart.</p><p><b>CONCLUSION</b>Inflammation exacerbates dyslipidemia mediated cardiac fibrosis in ApoE-/- mice partly through enhancing myocardial endothelial-to-mesenchymal transition.</p>

Application of systems biology to the study of chronic kidney disease / 中华医学杂志(英文版)

Chronic kidney disease (CKD) is a major public health problem that affects about 10% of the general population. Current approaches to characterize the category and progression of CKD are normally based on renal histopathological results and clinical parameters. However, this information is not sufficient to predict CKD progression risk reliably or to guide preventive interventions. Nowadays, the appearance of systems biology has brought forward the concepts of "-omics" technologies, including genomics, transcriptomics, proteomics, and metabolomics. Systems biology, together with molecular analysis approaches such as microarray analysis, genome-wide association studies (GWAS), and serial analysis of gene expression (SAGE), has provided the framework for a comprehensive analysis of renal disease and serves as a starting point for generating novel molecular diagnostic tools for use in nephrology. In particular, analysis of urinary mRNA and protein levels is rapidly evolving as a non-invasive approach for CKD monitoring. All these systems biological molecular approaches are required for application of the concept of "personalized medicine" to progressive CKD, which will result in tailoring therapy for each patient, in contrast to the "one-size-fits-all" therapies currently in use.

Influence of irbesartan on the urinary excretion of cytokines in patients with chronic kidney disease / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The non-hemodynamic effects of angiotensin receptor blocker (ARB) in the delay of progression of chronic kidney disease (CKD) remain unclear. In this study, we investigated the influence of irbesartan on the urinary excretion of cytokines in patients with CKD.</p><p><b>METHODS</b>In this randomized perspective clinical trial, different doses of irbesartan (150 mg/d and 300 mg/d) were given to two groups of patients in a cross-over design. Blood pressure (BP), creatinine clearance (Ccr) and 24-hour proteinuria were examined. Urinary excretion of cytokines was determined by human inflammatory cytokine antibody array. A two-fold change in spot intensity was considered significant.</p><p><b>RESULTS</b>Urinary excretion of cytokines (granulocyte colony stimulating factor (GCSF), intercellular cell adhesion molecule-1 (ICAM-1), interferon γ (IFN-γ), interleukin 1β (IL-1b), IL-2, IL-6, IL-8, IL-11, IL-15 and macrophage inflammatory protein 1d (MIP-1d)) in group B (irbesartan 300 mg/d) was significantly decreased in comparison to group A (irbesartan 150 mg/d) after 8-week treatment. In group A, 8 weeks of treatment induced a two- to nine-fold reduction in urinary cytokine levels (GCSF, GM-CSF, IFN-γ, IL-1a, IL-11, IL-12p40, MCP-2, MIP-1a), while increasing the dosage to 300 mg/d further decreased the excretion of GCSF, GM-CSF, IL-12p40, MCP-2 and MIP-1a by week 18. There was no significant difference in BP or Ccr between the two groups. However, 24-hour proteinuria was significantly reduced in both groups, and in group A the reduction was dose dependent.</p><p><b>CONCLUSION</b>Irbesartan offers additional renoprotection in a dose-dependent manner by reducing pro-inflammatory cytokines excretion in the urine of CKD patients.</p>