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

Training nephrologists from developing countries: does it have a positive impact?

In the past 25 years the International Society of Nephrology has sponsored 545 physicians from 83 developing countries to undertake nephrology training in renal units in the developed world. Data collected biennially from past fellows have demonstrated a very positive impact of the program on individual trainees and their home institutions. Many of the trainees have gone on to leadership positions in their home institutions, countries, and regions. Increasingly, fellowships are undertaken in selected developed centers within the fellow's own region, which increases the relevance and utility of the training to the fellow and the fellow's home institution, and lessens the risk of ‘brain drain’

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

Verapamil protects against progression of experimental chronic renal failure

Verapamil protects against progression of experimental chronic renal failure. Chronic administration of verapamil (Ver) decreases nephrocalcinosis and tubular ultrastructural abnormalities in the remnant model of chronic renal disease. In the present study, the effect of chronic Ver administration on renal function, renal histology and mortality after subtotal nephrectomy was examined. Fourteen days after staged subtotal nephrectomy rats were paired according to renal functional impairment, mean arterial pressure (MAP), and body weight. Rats were pair fed and received either Ver (0.1 µg/g sc bid, N = 10) or saline (0.1ml sc bid, N = 10) for up to 23 weeks. Both members of each pair were sacrificed shortly before the uremic death of controls. At sacrifice, rats treated with Ver had a lower serum creatinine (2.29 vs. 2.99 mg/dl, P < 0.05) and a higher creatinine clearance (318 vs. 164 µl/min, P < 0.05) than controls. In a second experiment, survival was superior in rats treated with Ver than in controls from week seven (P < 0.0025 by week 14). Serum creatinine was higher at week 10 in control rats (1.68 vs. 1.10 mg/dl, P < 0.05). MAP was no different between the two groups, irrespective of the time between Ver administration and the measurement of MAP. Histological damage and nephrocalcinosis were worse, and renal and myocardial calcium content was higher in controls. In conclusion, independent of any effect on systematic MAP, chronic administration of Ver protects against renal dysfunction, histological damage, nephrocalcinosis and myocardictl calcification, and improves survival in the remnant model of chronic 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

Low-light-level nonlinear optics with slow light

Electromagnetically induced transparency in an optically thick, cold medium creates a unique system where pulse-propagation velocities may be orders of magnitude less than $c$ and optical nonlinearities become exceedingly large. As a result, nonlinear processes may be efficient at low-light levels. Using an atomic system with three, independent channels, we demonstrate a quantum interference switch where a laser pulse with an energy density of $\sim23$ photons per $\lambda^2/(2\pi)$ causes a 1/e absorption of a second pulse.Comment: to be published in PR

Capturing and monitoring global differences in untreated and treated end-stage kidney disease, kidney replacement therapy modality, and outcomes

A large gap between the number of people with end-stage kidney disease (ESKD) who received kidney replacement therapy (KRT) and those who needed it has been recently identified, and it is estimated that approximately one-half to three-quarters of all people with ESKD in the world may have died prematurely because they could not receive KRT. This estimate is aligned with a previous report that estimated that >3 million people in the world died each year because they could not access KRT. This review discusses the reasons for the differences in treated and untreated ESKD and KRT modalities and outcomes and presents strategies to close the global KRT gap by establishing robust health information systems to guide resource allocation to areas of need, inform KRT service planning, enable policy development, and monitor KRT health outcomes

Lipopolysaccharide-pretreated plasmacytoid dendritic cells ameliorate experimental chronic kidney disease

Plasmacytoid dendritic cells play important roles in inducing immune tolerance, preventing allograft rejection, and regulating immune responses in both autoimmune disease and graft-versus-host disease. In order to evaluate a possible protective effect of plasmacytoid dendritic cells against renal inflammation and injury, we purified these cells from mouse spleens and adoptively transferred lipopolysaccharide (LPS)-treated cells, modified ex vivo, into mice with adriamycin nephropathy. These LPS-treated cells localized to the kidney cortex and the lymph nodes draining the kidney, and protected the kidney from injury during adriamycin nephropathy. Glomerulosclerosis, tubular atrophy, interstitial expansion, proteinuria, and creatinine clearance were significantly reduced in mice with adriamycin nephropathy subsequently treated with LPS-activated plasmacytoid dendritic cells as compared to the kidney injury in mice given naive plasmacytoid dendritic cells. In addition, LPS-pretreated cells, but not naive plasmacytoid dendritic cells, convert CD4+CD25− T cells into Foxp3+ regulatory T cells and suppress the proinflammatory cytokine production of endogenous renal macrophages. This may explain their ability to protect against renal injury in adriamycin nephropathy

Search for a W' boson decaying to a bottom quark and a top quark in pp collisions at sqrt(s) = 7 TeV

Results are presented from a search for a W' boson using a dataset corresponding to 5.0 inverse femtobarns of integrated luminosity collected during 2011 by the CMS experiment at the LHC in pp collisions at sqrt(s)=7 TeV. The W' boson is modeled as a heavy W boson, but different scenarios for the couplings to fermions are considered, involving both left-handed and right-handed chiral projections of the fermions, as well as an arbitrary mixture of the two. The search is performed in the decay channel W' to t b, leading to a final state signature with a single lepton (e, mu), missing transverse energy, and jets, at least one of which is tagged as a b-jet. A W' boson that couples to fermions with the same coupling constant as the W, but to the right-handed rather than left-handed chiral projections, is excluded for masses below 1.85 TeV at the 95% confidence level. For the first time using LHC data, constraints on the W' gauge coupling for a set of left- and right-handed coupling combinations have been placed. These results represent a significant improvement over previously published limits.Comment: Submitted to Physics Letters B. Replaced with version publishe

Search for the standard model Higgs boson decaying into two photons in pp collisions at sqrt(s)=7 TeV

A search for a Higgs boson decaying into two photons is described. The analysis is performed using a dataset recorded by the CMS experiment at the LHC from pp collisions at a centre-of-mass energy of 7 TeV, which corresponds to an integrated luminosity of 4.8 inverse femtobarns. Limits are set on the cross section of the standard model Higgs boson decaying to two photons. The expected exclusion limit at 95% confidence level is between 1.4 and 2.4 times the standard model cross section in the mass range between 110 and 150 GeV. The analysis of the data excludes, at 95% confidence level, the standard model Higgs boson decaying into two photons in the mass range 128 to 132 GeV. The largest excess of events above the expected standard model background is observed for a Higgs boson mass hypothesis of 124 GeV with a local significance of 3.1 sigma. The global significance of observing an excess with a local significance greater than 3.1 sigma anywhere in the search range 110-150 GeV is estimated to be 1.8 sigma. More data are required to ascertain the origin of this excess.Comment: Submitted to Physics Letters