Explore the vast range of titles available.

Comprehensive response is needed, across healthcare and beyond

Idiopathic membranous nephropathy is a major cause of the nephrotic syndrome in adults, but its etiologic basis is not fully understood. We investigated the genetic basis of biopsy-proven cases of idiopathic membranous nephropathy in a white population. We performed independent genomewide association studies of single-nucleotide polymorphisms (SNPs) in patients with idiopathic membranous nephropathy from three populations of white ancestry (75 French, 146 Dutch, and 335 British patients). The patients were compared with racially matched control subjects; population stratification and quality controls were carried out according to standard criteria. Associations were calculated by means of a chi-square basic allele test; the threshold for significance was adjusted for multiple comparisons (with the Bonferroni method). In a joint analysis of data from the 556 patients studied (398 men), we identified significant alleles at two genomic loci associated with idiopathic membranous nephropathy. Chromosome 2q24 contains the gene encoding M-type phospholipase A(2) receptor (PLA(2)R1) (SNP rs4664308, P=8.6×10(-29)), previously shown to be the target of an autoimmune response. Chromosome 6p21 contains the gene encoding HLA complex class II HLA-DQ alpha chain 1 (HLA-DQA1) (SNP rs2187668, P=8.0×10(-93)). The association with HLA-DQA1 was significant in all three populations (P=1.8×10(-9), P=5.6×10(-27), and P=5.2×10(-36) in the French, Dutch, and British groups, respectively). The odds ratio for idiopathic membranous nephropathy with homozygosity for both risk alleles was 78.5 (95% confidence interval, 34.6 to 178.2). An HLA-DQA1 allele on chromosome 6p21 is most closely associated with idiopathic membranous nephropathy in persons of white ancestry. This allele may facilitate an autoimmune response against targets such as variants of PLA2R1. Our findings suggest a basis for understanding this disease and illuminate how adaptive immunity is regulated by HLA.

EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: Evidence for a PPAR-γ–dependent mechanism. Recent studies have shown that fish oil, containing ω-3 polyunsaturated fatty acids (ω-3 PUFAs) eicosapentaenoic acid (EPA) (C20:5 ω 3), and docosahexaenoic acid (DHA) (C22:6 ω 3) retard the progression of renal disease, especially in IgA nephropathy (IgAN). Despite increasing knowledge of the beneficial effects of fish oils, little is known about the mechanisms of action of ω-3 PUFAs. It has been reported that activation of peroxisome proliferator-activated receptors (PPARs) inhibits production of proinflammatory cytokines. Both EPA and DHA have been shown to activate PPARs. The aim of this study was to examine if ω-3 PUFAs have anti-inflammatory effects via activation of PPARs in human renal tubular cells. An immortalized human proximal tubular cell line [human kidney-2 (HK-2) cells] was used in all experiments. Conditioned media was collected from ω-3 PUFAs- treated cells and subjected to enzyme-linked immunosorbent assay (ELISA). Total cellular RNA was isolated from the above cells for real-time quantitative polymerase chain reaction (PCR). Nuclear Extracts were prepared from the HK-2 cells for transcription factor activation assay. Both EPA and DHA at 10 μmol/L and 100 μmol/L concentrations effectively decreased lipopolysaccharide (LPS)-induced nuclear factor-kappaB (NF-κB) activation and monocyte chemoattractant protein-1 (MCP-1) expression. EPA and DHA also increased both PPAR-γ mRNA and protein activity (two- to threefold) in HK-2 cells. A dose of 100 μmol/L bisphenol A diglycidyl ether (BADGE) abolished the PPAR-γ activation induced by both EPA and DHA and removed the inhibitory effect of EPA and DHA on LPS-induced NF-κB activation in HK-2 cells. Overexpression of PPAR-γ further inhibited NF-κB activation compared to the control cells in the presence of EPA and DHA. Our data demonstrate that both EPA and DHA down-regulate LPS-induced activation of NF-κB via a PPAR-γ–dependent pathway in HK-2 cells. These results suggest that PPAR-γ activation by EPA and DHA may be one of the underlying mechanisms for the beneficial effects of fish oil.

Background Chronic systemic inflammation and abnormal free fatty acid metabolism are closely related to ectopic lipid deposition. In this study, we investigate if inflammation tissue-specifically disrupts lipogenesis and lipolysis in nonadipose tissues and adipose tissue, resulting in ectopic lipid deposition in C57BL/6J mice. Methods We used casein injection in C57BL/6J mice to induce a chronic systemic inflammatory stress in vivo. Serum was analyzed for free fatty acid and cytokines. Insulin sensitivities were evaluated by glucose and insulin tolerance tests. Liver, muscle, adipose tissues were taken for lipid analysis. Real-time polymerase chain reaction and western blotting were used to examine the gene and protein expression of molecules involved in adipogenesis and lipolysis in tissues. Results Casein injection elevated serum levels of IL-6 and SAA in mice, which are associated with increased lipid accumulation in liver and muscle, suggesting that chronic systemic inflammation induces ectopic lipid deposition in nonadipose tissues. The inflammatory stress upregulated mRNA and protein expression of sterol regulatory element binding protein 1, fatty acid synthase, and acetyl CoA carboxylase alpha, while inhibited these molecules expression in adipose. Interestingly, in the same experimental setting, inflammation increased triglyceride lipase and hormone-sensitive lipase expression in white adipose tissue. Inflammation also induced insulin resistance and increased serum free fatty acid levels in C57BL/6J mice. Conclusions Chronic systemic inflammation increased lipogenesis in nonadipose tissues and lipolysis in white adipose tissue, resulting in ectopic lipid deposition in nonadipose tissues. This disturbed free fatty acid homeostasis and caused insulin resistance in C57BL/6J mice.

We need to combine generalist and specialist skills