Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: Pathophysiology and indications

Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: Pathophysiology and indications. It is no a secret that we are confronted by an alarmingly increasing number of patients with progressive renal disease. There is ample evidence for the notion that angiotensin II (Ang II) is a major culprit in progression. The vasopeptide Ang II turned out to have also multiple nonhemodynamic pathophysiologic actions on the kidney, including proinflammatory and profibrogenic effects. Diverse complex Ang II generating systems have been identified, including specifically local tissue-specific renin-angiotensin systems (RAS). For example, proximal tubular cells have all components required for a functional RAS capable of synthesizing Ang II. On the other hand, Ang II is not the only effector of the RAS and other peptides generated by the RAS influence renal function and structure as well. Moreover, the discoveries that Ang II can be generated by enzymes other than angiotensin-converting enzyme (ACE) and that Ang II and other RAS derived peptides bind to various receptors with different functional consequences have further added to the complexity of this system. Several major clinical trials have clearly shown that ACE inhibitor treatment slows the progression of renal diseases, including in diabetic nephropathy. Well-controlled studies demonstrated that this effect is in part independent of blood pressure control. More recently, with Ang II type 1 receptor (AT1) receptor antagonists a similarly protective effect on renal function was seen in patients with type 2 diabetes. Neither ACE inhibitor treatment nor AT1 receptor blockade completely abrogate progression of renal disease. A recently introduced novel therapeutic approach is combination treatment comprising both ACE inhibitor and AT1 receptor antagonists. The rationale for this approach is based on several considerations. Small-scale clinical studies, mainly of crossover design, documented that combination therapy is more potent in reducing proteinuria in patients with different chronic renal diseases. Blood pressure as an important confounder was, however, significantly lower in the majority of this studies in the combination treatment arms compared to the respective monotherapies. In a recent prospective study Japanese authors avoided this confounder and demonstrated that combination therapy reduced hard end-points (end stage renal failure or doubling of serum creatinine concentration) by 50% compared to the respective monotherapies. This effect could not be explained by a more pronounced reduction of blood pressure in the combination therapy group. Although these results are encouraging, administration of combination therapy should be reserved currently to special high risk groups. Further studies are necessary to confirm these promising results. It is possible that combination therapy may increase the risk of hyperkalemia, particularly when with coadministered with medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) or spironolactone. In our opinion patients with proteinuria >1 g/day despite optimal blood pressure control under RAS-blocking monotherapy are a high-risk group which will presumably benefit from combination therapy

VLF-TE Messungen an betriebsgealterten Mittelspannungskabel - Abschlußbericht

Der Bericht bezieht sich auf das gleichnamige Projekt im BMBF-Programm zu anwendungsorientierter Forschung und Entwicklung an Fachhochschulen an der HTWG Konstanz: Das Monitoring und die Diagnose von Kabel- und Versorgungssystemen beruht zum größten Teil auf der Statistik. Es werden Daten aufgezeichnet und mit bereits ausgewerteten oder älteren Daten aus demselben System verglichen. Der Unterschied zwischen Monitoring und Diagnose ist, dass die Diagnose bei abgeschalteter Spannung erfolgt und das Monitoring ein ständiges Überwachen ist. Ziel der Teilentladungsmessungen an betriebsgealterten Mittelspannungskabel war es einen Vergleich von Teilentladungsmessungen mit 50Hz und 0,1Hz zu erstellen. Dabei wurden Teilentladungsmessungen bei stark voneinander abweichenden Prüfbedingungen untersucht. Des weiteren wurden Verlustleistungsmessungen (tan ð) bei verschiedenen Prüfobjekten mit 50Hz und 0,1Hz durchgeführt

Cretonthophilus tuberculatus , a remarkable new genus and species of hister beetle (Coleoptera: Histeridae) from Cretaceous Burmese amber

The early history of the beetle family Histeridae is still very obscure. In part this results from difficulty resolving phylogenetic relationships at deeper levels (Caterino & Vogler, 2002; McKenna et al., 2015a). But it is also partly a result of a sparse and poorly documented fossil record (Chatzimanolis et al., 2006). Here we describe a new genus and species of fossil histerid from Burmese amber (~99 mya), which helps to address both of these problems. Although histerid fossils have been reported from a variety of fossil localities and strata, relatively few have been adequately described. Until recently, the earliest described species of Histeridae was Onthophilus intermedius Handschin (1944) from the Oligocene phosphorites of Quercy, France (23–28 mya). A number of other taxa have been reported from more recent amber (Trypanaeus hispaniolus Chatzimanolis et al.(2006), early to mid-Miocene—15–20 mya— Dominican amber) or limestone fossils (e.g. numerous Hister spp. from mid-Miocene—13 mya—deposits at Öhningen; Heer, 1862). While fossil histerids have been noted from older deposits, such as the Eocene Florissant shales (34 mya; Scudder, 1886) and Baltic amber (37.7 mya; Swedo & Sontag, 2009), little has been adequately described. Chatzimanolis et al. (2006) therefore remarked, “In particular, it should be hoped that definitive Mesozoic histerids will be discovered, particularly in Cretaceous ambers, as such taxa might contribute most greatly to our understanding of early histerid evolution. ” The first such discovery was the recent description of Pantostictus burmanicus Poinar and Brown (2009) from Burmese amber (99 mya), which pushed the fossil record for the family significantly earlier. Here we describe as a second Mesozoic record for the family a new genus and species of Histeridae that is of the same Middle Cretaceous age as Pantostictus burmanicus, but is highly distinct morphologically. This new pecimen resembles modern Onthophilinae, but exhibits a number of distinctive characteristics. This fossil pushes the origin of the Histeridae considerably earlier, showing that not only had the family arisen by this time, but it had diversified considerably

Polen: Wirtschaftlicher Stabilitätsfaktor in Ostmitteleuropa?

Im Vergleich zu anderen ostmitteleuropäischen EU-Mitgliedsländern (MOEL = Mittel- und Osteuropa) und dem Gros der EU-15 Länder Westeuropas erscheint Polens Volkswirtschaft bemerkenswert stabil. Diese Position sollte jedoch nicht überschätzt werden. Die globale Finanz- und Wirtschaftskrise hat Strukturschwächen offenbart, die entschlossener Reformierung bedürfen. Innenpolitische Konstellationen erschweren jedoch eine aktive Reformpolitik. In einem optimistischen Szenario könnte Polen dennoch als relativer wirtschaftlicher Krisengewinner und erfolgreicher Reformer glaubwürdig versuchen, die wirtschaftliche EU-Agenda zu prägen

Albumin up-regulates the type II transforming growth factor-beta receptor in cultured proximal tubular cells1

Albumin up-regulates the type II transforming growth factor-beta receptor in cultured proximal tubular cells.BackgroundClinical and experimental observations suggest that proteinuria is not merely a marker of chronic nephropathies, but may also be involved in the progression to end-stage renal failure. Filtered proteins are taken up by tubular cells, and overwhelming this system may lead to tubular synthesis of various proinflammatory and profibrogenic cytokines, including transforming growth factor-beta (TGF-β). TGF-β acts by first binding to specific receptors. We studied in an in vitro system using a well-defined mouse proximal tubular cell line (MCT cells) whether fatty acid-free bovine albumin modulates expression of specific receptors for TGF-β.MethodsMCT (and LLC-PK1) cells were challenged in serum-free medium with different concentrations of albumin. Activation of a local renin-angiotensin system was tested by real-time polymerase chain reaction (PCR) for renin and angiotensinogen transcripts and determination of secreted angiotensin II (Ang II) by enzyme-linked immunosorbent assay (ELISA). Some cells were also treated with the AT1 receptor antagonist losartan. TGF-β receptor types I and II mRNA levels were determined by Northern analysis whereas protein abundance was measured by Western blots. To test for a functional consequence of up-regulated TGF-β receptors, MCT cells were preincubated with albumin and subsequently treated with low-dose TGF-β that normally does not induce collagen type IV expression by itself. Downstream signaling events were detected by Western blots for phosphorylated Smad2. Scatchard assays with [125I]TGF-β1 were performed to estimate affinity and number of specific binding sites. Different length TGF-β type II promoter constructs linked to CAT reporter were transiently transected into MCT cells to determine transcriptional activity.ResultsIncubation of MCT cells with 0.5 to 10 mg/mL albumin leads to an increase in type II TGF-β receptor mRNA and protein expression without influencing type I receptors. An increase in type II TGF-β receptor protein expression was detected after 12 hours of albumin incubation and was still detectable after 48 hours. The albumin-mediated increase in type II TGF-β receptor mRNA was attenuated in the presence of 1 μmol/L losartan, suggesting involvement of a local renin-angiotensin system. MCT cells treated with albumin significantly increased expression of angiotensinogen and renin transcripts and also secreted more Ang II into the culture supernatant. Analysis of transcriptional activity showed that promoter segments containing activating protein (AP-1)-binding sites are necessary for albumin-induced transcription of the TGF-β type II receptor. Binding assays revealed that albumin treatment significantly increased the overall binding sites as well as the affinity for TGF-β. This effect had functional consequences because MCT cells pretreated with albumin reacted with a stronger TGF-β–mediated phosphorylation of down-stream Smad2 and also increased collagen IV expression compared with control cells.ConclusionOur findings indicate that albumin up-regulates ligand-binding TGF-β receptors on cultured proximal tubular cells. Albumin-induced activation of local Ang II production appears to be responsible for this effect. This may amplify the matrix-stimulatory actions of TGF-β on tubular cells and could be a novel mechanism for how proteinuria exhibits pathophysiologic effects on tubular cells ultimately leading to tubulointerstitial fibrosis

Stability of gene rankings from RNAi screens

Motivation: Genome-wide RNA interference (RNAi) experiments are becoming a widely used approach for identifying intracellular molecular pathways of specific functions. However, detecting all relevant genes involved in a biological process is challenging, because typically only few samples per gene knock-down are available and readouts tend to be very noisy. We investigate the reliability of top scoring hit lists obtained from RNAi screens, compare the performance of different ranking methods, and propose a new ranking method to improve the reproducibility of gene selection. Results: The performance of different ranking methods is assessed by the size of the stable sets they produce, i.e. the subsets of genes which are estimated to be re-selected with high probability in independent validation experiments. Using stability selection, we also define a new ranking method, called stability ranking, to improve the stability of any given base ranking method. Ranking methods based on mean, median, t-test and rank-sum test, and their stability-augmented counterparts are compared in simulation studies and on three microscopy image RNAi datasets. We find that the rank-sum test offers the most favorable trade-off between ranking stability and accuracy and that stability ranking improves the reproducibility of all and the accuracy of several ranking methods. Availability: Stability ranking is freely available as the R/Bioconductor package staRank at http://www.cbg.ethz.ch/software/staRank. Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics onlin

MORG1—A Negative Modulator of Renal Lipid Metabolism in Murine Diabetes

Renal fatty acid (FA) metabolism is severely altered in type 1 and 2 diabetes mellitus (T1DM and T2DM). Increasing evidence suggests that altered lipid metabolism is linked to tubulointerstitial fibrosis (TIF). Our previous work has demonstrated that mice with reduced MORG1 expression, a scaffold protein in HIF and ERK signaling, are protected against TIF in the db/db mouse model. Renal TGF-ß1 expression and EMT-like changes were reduced in mice with single-allele deficiency of MORG1. Given the well-known role of HIF and ERK signaling in metabolic regulation, here we examined whether protection was also associated with a restoration of lipid metabolism. Despite similar features of TIF in T1DM and T2DM, diabetes-associated changes in renal lipid metabolism differ between both diseases. We found that de novo synthesis of FA/cholesterol and β-oxidation were more strongly disrupted in T1DM, whereas pathological fat uptake into tubular cells mediates lipotoxicity in T2DM. Thus, diminished MORG1 expression exerts renoprotection in the diabetic nephropathy by modulating important factors of TIF and lipid dysregulation to a variable extent in T1DM and T2DM. Prospectively, targeting MORG1 appears to be a promising strategy to reduce lipid metabolic alterations in diabetic nephropathy

Chronic anti-Thy-1 nephritis is aggravated in the nonclipped but not in the clipped kidney of Goldblatt hypertensive rats

Chronic anti-Thy-1 nephritis is aggravated in the nonclipped but not in the clipped kidney of Goldblatt hypertensive rats.BackgroundWe have previously shown that renovascular hypertension does not inhibit healing of the acute Thy-1 nephritis. To test whether a chronic model of the Thy-1 nephritis is more susceptible to high blood pressure, the repetitive hit model was evaluated in rats with 2-kidney, 1-clip Goldblatt hypertension.MethodsSix weeks after initiation of 2-kidney, 1-clip hypertension, chronic Thy-1 glomerulonephritis was induced in hypertensive rats by four consecutive injections of rabbit antiserum in weekly intervals. Renal structure and function were examined two weeks after the last injection. Glomerular binding of rabbit IgG as well as expression of transforming growth factor-beta (TGF-β), α-smooth muscle actin (α-SMA) and cyclooxygenase (COX)-1 and -2 were evaluated by Western blotting.ResultsSimilar glomerular deposition of rabbit IgG was detected in normotensive rats and in both kidneys of Goldblatt hypertensive rats indicating similar delivery and binding of the heterologous antibody. Induction of the repetitive Thy-1 model significantly enhanced glomerular damage in the nonclipped kidney and increased albuminuria. Surprisingly, no glomerular damage developed in the clipped kidney of nephritic hypertensive rats. In contrast, increased glomerular volume and increased expression of TGF-β, α-SMA as well as COX-1 and COX-2 were found in normotensive nephritic rats and in both kidneys of nephritic hypertensive rats.ConclusionGlomerular and tubulointerstitial damage of the chronic Thy-1 model is dramatically enhanced in the nonclipped kidneys of Goldblatt hypertensive rats. In contrast, the clipped kidney is completely protected from this immunological injury despite similar activation of glomerular cells, induction of TGF-β, COX-1 and COX-2 and glomerular hypertrophy