Der Einfluss endogener und exogener Faktoren auf Podozyten und Nierenfunktion

Einleitung: Humane Podozyten (hPC) stellen hochdifferenzierte Zellen dar, die einen elementaren Bestandteil der renalen Filtrationsbarriere bilden. Ihre intensive Erforschung in vitro ist erst seit wenigen Jahren möglich. Schädigungen der hPC durch Diabetes mellitus oder Bluthochdruck (Nephrosklerose) gehen häufig mit einem renalen Funktionsverlust einher. Das orale Biguanid-Antidiabetikum Metformin kann erhöhte Blutglukosespiegel und die Entwicklung einer Albuminurie vermindern. Angiotensin (Ang) II reguliert den Blutdruck und die intrarenale Hämodynamik. Diese Arbeit untersucht die Modifikation der intrazellulären Expression und Phosphorylierung von AMPK, Akt1 und des mechanistic Target of Rapamycin (mTOR) sowie das Zellüberleben von hPC durch Stimulation mit Glukose und Metformin. Darüber hinaus wird die Regulation des Glykoproteins Podoplanin (PDPN) in hPC durch AngII und miR-29b untersucht. Weiterhin wurde in einer in vivo Studie die Bedeutung von Testosteron auf die Entwicklung einer progressiven Albuminurie männlicher Tiere im Tiermodell der Munich Wistar Frömter (MWF) Ratte untersucht. Methodik: Ausdifferenzierte hPC wurden verschiedenen Konzentrationen von Glukose und Metformin oder AngII ausgesetzt. Die Transfektion mit small interfering RNA oder miRNA-Mimics erfolgte mittels Lipofectamine®2000. Proteinexpression und Phopshorylierungsgrad wurden durch Western Blots bestimmt. Zellapoptose und Zellviabilität wurden über funktionelle Assays erfasst. Männliche MWF-Ratten wurden in der zehnten Woche orchiektomiert. Die einzelnen Gruppen wurden scheinoperiert, mit Testosteron oder Testosteron plus Flutamid behandelt. Als Kontrolle dienten Wistar-Ratten. Bestimmt wurden der Testosterongehalt im Blut und die Albuminausscheidung im Urin (UAlb). Ergebnisse: Metformin hemmt die Phosphorylierung von AMPK und induziert die mTOR-Phosphorylierung. Unter Hochglukosebedingungen (HG)-Bedingungen regt Metformin die zelluläre Produktion von AMPK und Akt1 an, reduziert jedoch die zelluläre mTOR-Expression. Damit erhöht es das Zellüberleben unter HG signifikant. AngII induziert eine erhöhte miR-29b-Expression und reduziert die PDPN-mRNA und -Proteinexpression. Proapoptotische Effekte wie die Cytosol-C-Verteilung und die Caspase3-Aktivierung waren verstärkt. Die erhöhte UAlb bei MWF konnte durch durch Orchiektomie signifikant reduziert werden. Eine gleichzeitige Behandlung mit Testosteron plus Flutamid bewirkte bei MWF-Tieren eine weitere, signifikante Absenkung der UAlb. Schlussfolgerung: Im Rahmen der vorliegenden Arbeit konnte gezeigt werden, dass Metformin direkt auf hPC wirken und unabhängig von einer systemischen Absenkung des Blutzuckerspiegels proapoptotischen Effekte unter HG abschwächen sowie das Zellüberleben verbessern kann. Die zelluläre Integrität von hPC wird durch AngII beeinflusst. Über miRNA-29b wird die PDPN-Expression reguliert. PDPN ist für den Funktionserhalt, Stresstoleranz und Überleben der hPC relevant. Darüber hinaus konnte nachgewiesen werden, dass Testosteron in die pathologische Albuminurieentwicklung bei männlichen Ratten involviert ist. Um aus diesen Studien mögliche renoprotektive Maßnahmen für die Klinik abzuleiten, sind weiterführende Arbeiten nötig.Introduction: Human podocytes (hPC) are highly differentiated cells and representing an important part of the renal filtration barrier. Methods to study hPC in in vitro were only recently established. Damage to hPCs due to diabetesmellitus or hypertension frequently leads to renal impairment. The oral biguanid Metformin can reduce blood glucose levels and prevent the development of albuminuria. Angiotensin (Ang) II regulates blood pressure and intrarenal hemodynamic. This work examines the modification of expression and phosphorylation of AMPK, Akt1 and mTOR as well as the cell survival of hPC after stimulation with glucose and Metformin. Furthermore, the regulation of glycoprotein podoplanin (PDPN) in hPC through Ang II and miR-29b is examined. Additionally, an in vivo study investigated the effect of testosterone on the development of progressive albuminuria in male Munich Wistar Frömter (MWF) rats. Methods: Differentiated hPC were exposed to various concentrations of glucose and Metformin or AngII. The transfection with small interfering RNA or miRNA-mimics was done with Lipofectamine®2000. Protein expression and phosphorylation were determined with Western blots. Cell apoptosis and viability were measured with functional assays. Male MWF rats were orchiectomized at ten weeks of age. MWF were sham operated or treated with either testosterone or testosterone plus flutamid. Wistar rats were used as controls. Testosterone serum levels and urinary albumin excretion (UAlb) were measured. Results: Metformin inhibits AMPK phosphorylation and induces mToR phosphorylation. Under high glucoses conditions (HG) metformin stimulates cellular production of AMPK and Akt1 but reduces cellular mTOR expression. This significantly increases cell survival under HG. AngII induces miR-29b expression and reduces cellular mRNA and protein expression of PDPN. Proapoptotic effects such as Cytosol-C distribution and Caspase3 activation were elevated. Testosterone serum concentrations and increased albuminuria in male MWF was significantly reduced by orchiectomy. Concomitant treatment with testosterone plus lead to a further significant decrease of UAlb in MWF. Conclusion: Metformin affects hPC directly. Metformin reduces apoptosis under HG and increases cell survival independently from systemic blood sugar reduction. Cellular integrity of hPC is influenced by AngII. PDPN expression is regulated through miRNA-29b. PDPN is of relevance for function, stress tolerance and survival of hPC. Furthermore, testosterone is involved in the development of increased albuminuria in male rats. To generate future renoprotective applications from these studies for clinical use, further investigation is required

Fault step-over rheology and its effect on earthquake rupture propagation

We study the effects that damage and porosity may have on rupture propagation by reducing material strength and increasing both on-fault and off-fault dissipation of earthquake energy within the step-over zone. We find that the presence of damage and porosity in step-over zones significantly reduce the width of step-overs that may be considered as rupture barriers, and therefore greatly increases fault-system stability. The results are of practical importance to seismic hazard analysis where probable length of rupture and earthquake magnitude are estimated based on mapped active faults. The results portray the importance of assessing the material state and characteristics of fault step-over zones, rather than only the general geometry of the step-over

The Flypaper Effect in Germany: An East-West Comparison

We investigate the effect of general-purpose transfers on different expenditure categories and tax rates in the municipalities of Saxony (eastern Germany) and North Rhine-Westphalia (western Germany). Findings from the panel data analysis suggest the existence of the “flypaper effect” – municipalities use transfers to increase expenditures but do not reduce taxes. For most expenditure subcategories the estimated coefficients are alike, suggesting similarity of spending priorities in the two federal states despite the differences in the transfer dependency. Targeted support of eastern municipalities could potentially explain few identified differences in the spending behavior

Electoral Externalities in Federations - Evidence from German Opinion Polls

Der Erfolg von Parteien unterschiedlicher politischer Ebenen ist stark voneinander abhängig. Föderale Wahlen beeinflussen regionale Wahlentscheidungen und umgekehrt (Wahlexternalitäten). In diesem Aufsatz identifizieren wir Wahlexternalitäten zwischen Deutschland insgesamt und Berlin für vier Parteien. Dafür benutzen wir Wahlumfragen. Wahlexternalitäten erklären zwischen 10% und 30% der Variation der jeweils anderen politischen Ebene. Die Effekte sind höchst heterogen zwischen den Parteien

Electoral Externalities in Federations - Evidence from German Opinion Polls

Party performance in state and federal elections is highly interdependent. Federal elections impact regional voting dynamics and vice versa (electoral externalities). We quantify the extent of simultaneous electoral externalities between two layers of government. We apply vector autoregressions with predetermined variables to unique opinion poll data for the German state of Berlin and the federal level in Germany. State voting intentions for the state and for the federal parliament are the endogenous variables; the federal election trend is treated as predetermined. Our results suggest that shocks in federal parliament voting intention impact state parliament voting intention, but – as a new finding – to the same extent also vice versa. Externalities account for around 10% to 30% of variation at the other level of government. The effects differ across parties. Electoral externalities are less pronounced for the conservative party, but increase in times of government. The opposite holds true for left-wing parties

Semantic Integration of Identity Data Repositories

With the continuously growing number of distributed and heterogeneous IT systems there is the need for structured and efficient identity management (IdM) processes. This implies that new users are created once and then the information is distributed to all applicable software systems same as if changes on existing user objects occur. The central issue is that there is no generally ac-cepted standard for handling this information distribution because each system has its own internal representation of this data. Our approach is to give a se-mantic definition of the digital user objects attributes to ease the mapping process of an abstract user object to the concrete instantiation of each software system. Therefore we created an ontology to define the mapping of users at-tributes as well as an architecture which enables the semantic integration of identity data repositories. Our solution has been tested in an implementation case study

Permafrost - physical aspects and carbon cycling, databases and uncertainties

Permafrost is defined as ground that remains below 0°C for at least 2 consecutive years. About 24% of the northern hemisphere land area is underlain by permafrost. The thawing of permafrost has the potential to influence the climate system through the release of carbon (C) from northern high latitude terrestrial ecosystems, but there is substantial uncertainty about the sensitivity of the C cycle to thawing permafrost. Soil C can be mobilized from permafrost in response to changes in air temperature, directional changes in water balance, fire, thermokarst, and flooding. Observation networks need to be implemented to understand responses of permafrost and C at a range of temporal and spatial scales. The understanding gained from these observation networks needs to be integrated into modeling frameworks capable of representing how the responses of permafrost C will influence the trajectory of climate in the future

A very large deployable space antenna structure based on pantograph tensioned membranes

This paper provides investigation results on the membrane technology development of a high accuracy (low deformation and high eigenfrequency) membrane antenna structure and its demonstrator for space application

The Effect of Land Consumption on Municipal Tax Revenue: Evidence from Bavaria

This paper aims to quantify the municipal tax revenue effects of built-up area increases. The assumed existence of these effects is one of the key reasons for ongoing land consumption on the side of the municipalities. Some previous case studies however suggested that these effects might be not large enough especially in rural municipalities and would thus make land development not profitable. We estimate the effect of built-up industrial and commercial (BIC) area change on the business tax revenues in cross-sectional instrumental variable (IV) estimations. Based on detailed data for Bavaria, we find a significant and positive tax revenue effect of an increase in municipal BIC area. There exist strong differences in the size of this effect between urban and rural municipalities. The largest effects are generated by the BIC area in the large cities and become substantially smaller when these are dropped from the sample. Based on these findings, we reflect on the tradable planning permits (TPP) scheme recently discussed in the land use literature in the context of policies aiming to limit land consumption. Furthermore, we relate our estimates to the average municipal costs for land development and execute a number of robustness checks

Towards representing thermokarst processes in land surface models

Large-scale Earth system and land surface models often lack an adequate representation of subgrid-scale processes in permafrost landscapes. Small-scale processes such as thermokarst formation might, however, considerably impact the energy and carbon budgets in way which is not resolved within large-scale models. Since a spatially high-resolved simulation of such processes is not feasible, novel techniques for up-scaling subgrid processes are demanded. Within this work a one-dimensional model of the ground thermal regime of land surfaces, CryoGrid 3, is employed to conceptually represent small-scale features of permafrost landscapes, particularly those related to thermokarst. For example, the model has been shown to adequately describe the degradation of permafrost underneath waterbodies in a warming climate. Using tiling approaches such point-wise realizations can be up-scaled in a statistical way in order to represent larger land surface units. The model development is closely linked to field campaigns to the Lena River Delta in Siberia which offers very diverse land surface features such as polygonal tundra and thermos-erosional valleys. These features are related to the region’s diverse soil stratigraphies, in particular the occurrence of ice-rich ground. Combining field measurements with modelling ultimately allows an improvement in the qualitative and quantitative understanding of the typical geomorphological processes in permafrost landscapes and their representation in large-scale models