Proximal tubule cells stimulated by lipopolysaccharideinhibit macrophage activation

Proximal tubule cells stimulated by lipopolysaccharide inhibit macrophage activation.BackgroundTubule cells can produce a variety of cytokines, extracellular matrix (ECM) components, and adhesion molecules in vitro and in vivo. It is generally assumed that stimulated tubule cells are proinflammatory and at least partially responsible for interstitial inflammation. However, the overall effect of tubular cells on interstitial cells is unknown. In this study, pro- and anti-inflammatory cytokine production and net effects on macrophages of tubule cells activated by lipopolysaccharide (LPS) were examined.MethodsTubule cells stimulated with LPS expressed tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-12, monocyte chemoattractant protein-1 (MCP-1), IL-10, and transforming growth factor-β (TGF-β). Conditioned media werecollected from confluent monolayers of rat tubule cells stimulated, or not, by LPS for 4 and 18 hours, respectively. Macrophages were cultured with conditioned media and/or LPS (0.5 μg/mL) for 18 hours.ResultsTNF-α and IL-lβ mRNA of macrophages stimulated by LPS increased more than fivefold when cultured with control conditioned media from unstimulated tubule cells. Surprisingly, TNF-α and IL-lβ levels of macrophages stimulated by LPS were not increased when cultured with conditioned media from activated tubule cells. Neutralizing antibodies to IL-10 and TGF-β were used to define the inhibitory component(s) in conditioned medium. Anti-IL-10, but not anti-TGF-β, abolished partially the inhibitory effects of conditioned media on macrophages.ConclusionTubule cells produce both pro- and anti-inflammatory cytokines and the net effect, partially explained by IL-10, of tubule cells activated with LPS is to inhibit activity of macrophages. Thus, the net effect of activated tubule cells on interstitial pathology may in certain circumstances, be anti- rather than pro-inflammatory

Role of CD8+ cells in the progression of murine adriamycin nephropathy

Role of CD8+ cells in the progression of murine adriamycin nephropathy.BackgroundMany studies have shown that interstitial inflammation in human and experimental renal disease is characterized by T-cell infiltration, but published data on the involvement of inflammatory cell subsets in progressive tubulointerstitial lesions are often conflicting. A previous study suggested a role for cytotoxic T lymphocytes in the damaging effect of CD4+ T-cell depletion in murine adriamycin (ADR) nephropathy, a model of focal segmental glomerulosclerosis (FSGS), and tubulointerstitial inflammation. The aim of this study was to investigate the role of CD8+ cells in this model.MethodsMale BALB/c mice were treated with five intraperitoneal injections of anti-CD8 monoclonal antibody (mAb), beginning from five days after ADR treatment, when overt proteinuria was established. Seven mice in each of groups A (ADR + mAb), B (ADR only), and C (saline treated, age matched) were sacrificed at week 6. Changes in renal function and histopathological features were assessed. Tubulointerstitial inflammation and glomerular inflammation were examined immunohistochemically.ResultsmAb treatment reduced CD8+ cell levels to <2% of normal in spleen. Proteinuria in group A was no different from that in group B at week 6, but was markedly higher than in group C. Creatinine clearance was significantly ameliorated by anti-CD8 treatment (71.8 ± 4.9 μL/min vs. 29.2 ± 2.8 in group B and 81.9 ± 3.7 in group C). Morphometric analysis showed less FSGS in group A compared with group B (6.5 ± 1.9 vs. 13.0 ± 2.8, P < 0.001), as well as less tubular atrophy (indicated by increased ratio of tubule cell height to tubular diameter, 0.25 ± 0.24 in group A vs. 0.04 ± 0.02 in group B, P < 0.05). CD8 depletion also reduced interstitial expansion (6.3 ± 2.2% vs. 16.4 ± 3.1 in group B, P < 0.001) and fibrosis (P < 0.01). Macrophage infiltration in tubulointerstitium was less in group A than in group B (P = 0.052). The number of interstitial CD4+ cells appeared to increase after anti-CD8 treatment, but was not statistically different between groups A and B.ConclusionAnti-CD8 treatment protects against renal functional and structural injury in this murine model of chronic proteinuric renal disease

Can murine diabetic nephropathy be separated from superimposed acute renal failure?

Can murine diabetic nephropathy be separated from superimposed acute renal failure?BackgroundStreptozotocin (STZ) is commonly used to induce diabetes in experimental animal models, but not without accompanying cytotoxic effects. This study was undertaken to (1) determine an optimal dose and administration route of STZ to induce diabetic nephropathy in wild-type mice but without the concurrent acute renal injury resulting from cytotoxic effects of STZ and (2) evaluate the pattern of tubular injury and interstitial inflammation in this model.MethodsMale Balb/c mice received either (1) STZ (225mg/kg by intraperitoneal injection.); or (2) two doses of STZ 5 days apart (150mg/150mg/kg; 75mg/150mg/kg; 75mg/75mg/kg; and 100mg/100mg/kg by intravenous injection). Another strain of mice, C57BL/6J, also received STZ (200mg/kg intravenously or intraperitoneally). Renal function and histology were examined at weeks 1, 2, 4, and 8 after induction of diabetes. In initial optimization studies, animals were sacrificed at week 1 or week 2 and histology examined for acute renal injury.ResultsFollowing a single intraperitoneal injection of 225mg/kg of STZ, only two thirds of animals developed hyperglycemia, yet the model was associated with focal areas of acute tubular necrosis (ATN) at week 2. ATN was also observed in C57BL/6J mice given a single intravenous or intraperitoneal dose of STZ (200mg/kg), at week 2 post-diabetes. At an optimal diabetogenic dose and route (75mg/150mg/kg by intravenous injection 5 days apart), all mice developed diabetes and no ATN was observed histologically. However, even with this regimen, glomerular filtration rate (GFR) was significantly impaired from week 2. This regimen was accompanied by progressive histologic changes, including tubular and glomerular hypertrophy, mesangial area expansion, as well as interstitial macrophage, CD4+ and CD8+ T-cell accumulation.ConclusionBy careful optimization of STZ dose, a stable and reproducible diabetic murine model was established. However, even in this optimized model, renal functional impairment was observed. The frequency of ATN and functional impairment casts doubt on conclusions about experimental diabetic nephropathy drawn from reports in which ATN has not been excluded rigorously

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium

Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. Methods:Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. Results:Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95 confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. Conclusion:Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2. © 2014 Cancer Research UK

Capacitance-voltage measurements on MOS capacitors fabricated on polycrystalline silicon wafers

Applied Surface Science592105-110ASUS

Tardive dyskinesia in elderly psychiatric patients in Singapore

Australian and New Zealand Journal of Psychiatry251119-122ANZP

Quasi-Fermi level variation in the space-charge region of a grain boundary

10.1088/0022-3727/18/4/011Journal of Physics D: Applied Physics184671-67

Adaptive library-based device performance-driven optical proximity correction

10.1049/el.2010.2724Electronics Letters467513-515ELLE

Dynamic game difficulty scaling using adaptive behavior-based AI

10.1109/TCIAIG.2011.2158434IEEE Transactions on Computational Intelligence and AI in Games34289-30