Defining the Molecular Character of the Developing and Adult Kidney Podocyte

BACKGROUND: The podocyte is a remarkable cell type, which encases the capillaries of the kidney glomerulus. Although mesodermal in origin it sends out axonal like projections that wrap around the capillaries. These extend yet finer projections, the foot processes, which interdigitate, leaving between them the slit diaphragms, through which the glomerular filtrate must pass. The podocytes are a subject of keen interest because of their key roles in kidney development and disease. METHODOLOGY/PRINCIPAL FINDINGS: In this report we identified and characterized a novel transgenic mouse line, MafB-GFP, which specifically marked the kidney podocytes from a very early stage of development. These mice were then used to facilitate the fluorescent activated cell sorting based purification of podocytes from embryos at E13.5 and E15.5, as well as adults. Microarrays were then used to globally define the gene expression states of podocytes at these different developmental stages. A remarkable picture emerged, identifying the multiple sets of genes that establish the neuronal, muscle, and phagocytic properties of podocytes. The complete combinatorial code of transcription factors that create the podocyte was characterized, and the global lists of growth factors and receptors they express were defined. CONCLUSIONS/SIGNIFICANCE: The complete molecular character of the in vivo podocyte is established for the first time. The active molecular functions and biological processes further define their unique combination of features. The results provide a resource atlas of gene expression patterns of developing and adult podocytes that will help to guide further research of these incredible cells

Renal Thrombotic Microangiopathy in Mice with Combined Deletion of Endocytic Recycling Regulators EHD3 and EHD4

Eps15 Homology Domain-containing 3 (EHD3), a member of the EHD protein family that regulates endocytic recycling, is the first protein reported to be specifically expressed in the glomerular endothelium in the kidney; therefore we generated Ehd3–/– mice and assessed renal development and pathology. Ehd3–/– animals showed no overt defects, and exhibited no proteinuria or glomerular pathology. However, as the expression of EHD4, a related family member, was elevated in the glomerular endothelium of Ehd3–/– mice and suggested functional compensation, we generated and analyzed Ehd3–/–; Ehd4–/– mice. These mice were smaller, possessed smaller and paler kidneys, were proteinuric and died between 3–24 weeks of age. Detailed analyses of Ehd3–/–; Ehd4–/– kidneys demonstrated thrombotic microangiopathy (TMA)-like glomerular lesions including thickening and duplication of glomerular basement membrane, endothelial swelling and loss of fenestrations. Other changes included segmental podocyte foot process effacement, mesangial interposition, and abnormal podocytic and mesangial marker expression. The glomerular lesions observed were strikingly similar to those seen in human pre-eclampsia and mouse models of reduced VEGF expression. As altered glomerular endothelial VEGFR2 expression and localization and increased apoptosis was observed in the absence of EHD3 and EHD4, we propose that EHD-mediated endocytic traffic of key surface receptors such as VEGFR2 is essential for physiological control of glomerular function. Furthermore, Ehd3–/–; Ehd4–/– mice provide a unique model to elucidate mechanisms of glomerular endothelial injury which is observed in a wide variety of human renal and extra-renal diseases

Gene Expression Programs of Mouse Endothelial Cells in Kidney Development and Disease

Endothelial cells are remarkably heterogeneous in both morphology and function, and they play critical roles in the formation of multiple organ systems. In addition endothelial cell dysfunction can contribute to disease processes, including diabetic nephropathy, which is a leading cause of end stage renal disease. In this report we define the comprehensive gene expression programs of multiple types of kidney endothelial cells, and analyze the differences that distinguish them. Endothelial cells were purified from Tie2-GFP mice by cell dissociation and fluorescent activated cell sorting. Microarrays were then used to provide a global, quantitative and sensitive measure of gene expression levels. We examined renal endothelial cells from the embryo and from the adult glomerulus, cortex and medulla compartments, as well as the glomerular endothelial cells of the db/db mutant mouse, which represents a model for human diabetic nephropathy. The results identified the growth factors, receptors and transcription factors expressed by these multiple endothelial cell types. Biological processes and molecular pathways were characterized in exquisite detail. Cell type specific gene expression patterns were defined, finding novel molecular markers and providing a better understanding of compartmental distinctions. Further, analysis of enriched, evolutionarily conserved transcription factor binding sites in the promoters of co-activated genes begins to define the genetic regulatory network of renal endothelial cell formation. Finally, the gene expression differences associated with diabetic nephropathy were defined, providing a global view of both the pathogenic and protective pathways activated. These studies provide a rich resource to facilitate further investigations of endothelial cell functions in kidney development, adult compartments, and disease

Leader Election in Rings with Homonyms.

International audienceConsidering the case of homonyms processes (some processesmay share the same identifier) on a ring, we give here a necessary andsufficient condition on the number of identifiers to enable leader election.We prove that if l is the number of identifiers then message-terminatingelection is possible if and only if l is greater than the greatest properdivisor of the ring size even if the processes do not know the ring size.If the ring size is known, we propose a process-terminating algorithmexchanging O(n log(n)) messages that is optimal

Gendered Sexual Uses of Alcohol and Associated Risks: A Qualitative Study of Nigerian University Students

Background: Alcohol misuse among young people is a global phenomenon. In many countries, young people engage in heavy drinking and this exacerbates risky sexual behaviour. In Nigeria, alcohol held multiple roles in the traditional era but was mainly consumed by adult males for pleasure. Adult females and young people were culturally constrained from drinking in most communities. In contemporary Nigeria, young people’s drinking is increasing, and many engage in sexual intercourse under the influence of alcohol. Methods: This study draws on the traditional gender and social sexual scripts to explore the factors that motivate young people to use alcohol for sexual purposes. In-depth interviews were conducted with 19 to 23-year old male and female undergraduate students from a Nigerian university. Thematic analysis was conducted with the aid of NVivo 10 software. Results: Men drink to become confident to initiate sexual relationships, stimulate sexual urges, prolong erection, increase sexual satisfaction and become more aggressive during sexual intercourse. Women also drink to be bold in initiating sexual relationships, for sexual arousal and to increase satisfaction. Relatedly, not every brand of alcohol is used for sexual purposes. For example, while men use ‘herbal’ alcoholic beverages and a mixture of locally-produced gin and marijuana, women use champagne and other flavoured alcoholic beverages. The results also revealed that young people use alcohol or salt in a bid to prevent conception after sexual intercourse. Conclusions: Adherence to the traditional gender (masculinity) and social sexual scripts amongst men and the enactment of what appears to be a new form of femininity script amongst women contribute to a culturally specific understanding of the motivations to use alcohol for sexual purposes. Evidence-based strategies should be employed to distribute information about the consequences of sexual intercourse under the influence of alcohol