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An intact renin-angiotensin system involving ANG II type 1 (AT1) receptors is crucial for normal kidney development. It is still unclear in which cell types AT1receptor signaling is required for normal kidney development, maturation, and function. Because all kidney cells deriving from stroma progenitor cells express AT1receptors and because stromal cells fundamentally influence nephrogenesis and tubular maturation, we investigated the relevance of AT1receptors in stromal progenitors and their descendants for renal development and function. For this aim, we generated and analyzed mice with conditional deletion of AT1Areceptor in the FoxD1 cell lineage in combination with global disruption of the AT1Breceptor gene. These FoxD1-AT1ko mice developed normally. Their kidneys showed neither structural nor functional abnormalities compared with wild-type mice, whereas in isolated perfused FoxD1-AT1ko kidneys, the vasoconstrictor and renin inhibitory effects of ANG II were absent. In vivo, however, plasma renin concentration and renal renin expression were normal in FoxD1-AT1ko mice, as were blood pressure and glomerular filtration rate. These findings suggest that a strong reduction of AT1receptors in renal stromal progenitors and their descendants does not disturb normal kidney development.

Political parties can play a crucial role in linking citizen preferences to political decision making, but have been criticized for not accomplishing this task. In an attempt to address this linkage problem and enhance policy representation, political parties have recently opened up their decision-making processes and promoted online participation among their members and supporters; for example, by establishing online platforms that allow citizens and party members to discuss policy issues and generate policy proposals. However, in most instances, participation is low. Drawing on the case of the German Green Party and applying three well-established models of offline political participation, the article examines why only some party members and supporters use these channels to communicate their preferences. Comparing users and nonusers, we conclude that socioeconomic resources or attitudes alone cannot explain differences in participation. Instead, participation is motivated by process-related and ideological incentives.

An intact renin-angiotensin system involving ANG II type 1 (AT

Politische Parteien sind verstarkt dazu ubergegangen, politische Beteiligung uber das Internet zu ermoglichen, beispielsweise mithilfe von Online-Plattformen, die Burgern und Parteimitgliedern erlauben, politische Fragen zu diskutieren und gemeinsam an Dokumenten wie Wahlprogrammen zu arbeiten. Jedoch nehmen an solchen Beteiligungsformaten oft nur wenige Personen teil. Anhand des Einsatzes einer solchen Plattform seitens der Partei Die Grunen untersucht der Beitrag, warum einige Parteimitglieder von dieser Beteiligungsmoglichkeit Gebrauch gemacht haben, andere wiederum nicht. Dabei wird auf traditionelle Modelle zur Erklarung von politischer Beteiligung zuruckgegriffen und gezeigt, dass innerparteiliche Online-Beteiligung weniger durch Ressourcen oder Einstellungen motiviert wird. Vielmehr ist entscheidend, dass es starke Anreize zur Beteiligung gibt.

You cannot form a state with the Internet—or can you? In contrast to post-territorial expectations from the early days of the Internet, the state seems to be increasingly in demand when it comes to coming to terms with the digital revolution. What is more, state structures have never been irrelevant in terms of the Internet but have influenced both it and digitalisation since their beginnings. This book explores the intriguing relationship between the Internet and the state in depth from an interdisciplinary perspective that includes political science, legal studies and communication studies. By examining sovereignty, privacy and security, the contributions it contains address the fundamental understandings and functions of the state. They deal with regulatory areas that have changed dynamically in the digital era: data protection, the administration of critical Internet resources and the regulation of media content. Finally, they also consider the changes to the players involved in this field and the courses of action open to them: parties and political communication, e-government and e-participation. With contributions by Isabelle Borucki, Andreas Busch, Myriam Dunn Cavelty, Florian Egloff, Katharina Gerl, Paula Helm, Norbert Kersting, Jan Niklas Kocks, Julia Pohle, Claudia Ritzi, Wolf J. Schünemann, Sandra Seubert, Thorsten Thiel, Martin Warnke and Alexandra Zierold.

Hypoxia-inducible factor (HIF)-2–triggered erythropoietin production in renal interstitial fibroblast–like cells is the physiologically relevant source of erythropoietin for regulating erythropoiesis. During renal fibrosis, these cells transform into myofibroblasts and lose their ability to produce sufficient erythropoietin leading to anemia. To find if other cells for erythropoietin production might exist in the kidney we tested for the capability of nonepithelial glomerular cells to elaborate erythropoietin. Therefore, HIF transcription factors were stabilized by cell-specific deletion of the von Hippel–Lindau ( VHL ) gene. Inducible deletion of VHL in glomerular connexin40-expressing cells (endothelial, renin-expressing, and mesangial cells) markedly increased glomerular erythropoietin mRNA expression levels, plasma erythropoietin concentrations, and hematocrit values. These changes were mimicked by inducible cell-specific VHL deletion in renin-expressing and in mesangial cells but not in endothelial cells. The increases of erythropoietin production were absent, when VHL was co-deleted with HIF-2. The induction of glomerular erythropoietin expression was associated with the downregulation of juxtaglomerular renin expression, again in a HIF-2-dependent manner. Thus, VHL deletion in renin-expressing and in mesangial cells induces the capability to produce relevant amounts of erythropoietin and to suppress renin expression in the adult kidney if HIF-2 is stabilized.

On the basis of previous observations that deletion of the von Hippel–Lindau protein (pVHL) in juxtaglomerular (JG) cells of the kidney suppresses renin and induces erythropoietin expression, this study aimed to characterize the events underlying this striking change of hormone expression. We found that renin cell-specific deletion of pVHL in mice leads to a phenotype switch in JG cells, from a cuboid and multiple vesicle-containing form into a flat and elongated form without vesicles. This shift of cell phenotype was accompanied by the disappearance of marker proteins for renin cells (e.g., aldo-keto reductase family 1, member 7 and connexin 40) and by the appearance of markers of fibroblast-like cells (e.g., collagen I, ecto-5′-nucleotidase, and PDGF receptor-β). Furthermore, hypoxia-inducible transcription factor-2α (HIF-2α) protein constitutively accumulated in these transformed cells. Codeletion of pVHL and HIF-2α in JG cells completely prevented the phenotypic changes. Similar to renin expression in normal JG cells, angiotensin II negatively regulated erythropoietin expression in the transformed cells. In summary, chronic activation of HIF-2 in renal JG cells leads to a reprogramming of the cells into fibroblast-like cells resembling native erythropoietin-producing cells located in the tubulointerstitium.

Intrauterine hypoxia is a reason for impaired kidney development. The cellular and molecular pathways along which hypoxia exerts effects on nephrogenesis are not well understood. They are likely triggered by hypoxia-inducible transcription factors (HIFs), and their effects appear to be dependent on the cell compartment contributing to kidney formation. In this study, we investigated the effects of HIF activation in the developing renal stroma, which also essentially modulates nephron development from the metanephric mesenchyme. HIF activation was achieved by conditional deletion of the von Hippel–Lindau tumor suppressor (VHL) protein in the forkhead box FOXD1 cell lineage, from which stromal progenitors arise. The resulting kidneys showed maturation defects associated with early postnatal death. In particular, nephron formation, tubular maturation, and the differentiation of smooth muscle, renin, and mesangial cells were impaired. Erythropoietin expression was strongly enhanced. Codeletion of VHL together with HIF2A but not with HIF1A led to apparently normal kidneys, and the animals reached normal age but were anemic because of low erythropoietin levels. Stromal deletion of HIF2A or HIF1A alone did not affect kidney development. These findings emphasize the relevance of sufficient intrauterine oxygenation for normal renal stroma differentiation, suggesting that chronic activity of HIF2 in stromal progenitors impairs kidney development. Finally, these data confirm the concept that normal stroma function is essential for normal tubular differentiation.

PDGFR-β-expressing cells of the kidneys are considered as a relevant site of erythropoietin (EPO) production. The origin of these cells, their contribution to renal EPO production, and if PDGFR-β-positive cells in other organs are also capable to express EPO are less clear. We addressed these questions in mice, in which hypoxia-inducible transcription factors were stabilized in PDGFR-β(+) cells by inducible deletion of the von Hippel-Lindau (Vhl) protein. Vhl deletion led to a 600-fold increase of plasma EPO concentration, 170-fold increase of renal EPO messenger RNA (mRNA) levels, and an increase of hematocrit values up to 70 %. Intrarenal localization of EPO-expressing cells coincided with the zonal heterogeneity and distribution of cells expressing PDGFR-β. Amongst a variety of extrarenal organs only adrenal glands showed significant EPO mRNA expression after Vhl deletion in PDGFR-β(+) cells. EPO mRNA, plasma EPO, and hematocrit fell to subnormal values if HIF-2α, but not HIF-1α, was deleted either alone or in combination with Vhl in PDGFR-β(+) cells. Treatment of mice with a prolyl-hydroxylase inhibitor caused an increase of EPO mRNA abundance and plasma EPO concentrations in wild-type mice and in mice lacking HIF-1α in PDGFR-β(+) cells but exerted no effect in mice lacking HIF-2α in PDGFR-β(+) cells. These findings suggest that PDGFR-β(+) cells are the only relevant site of EPO expression in the kidney and that HIF-2 is the essential transcription factor triggering EPO expression therein. Moreover, our findings suggest that PDGFR-β(+) cells elaborating EPO might arise from the metanephric mesenchyme, rather than from the neural crest.