Pathophysiological roles of ALDO/MR in the kidney
Working Group 4
Key outcomes of WG4 will be the elucidation of key regulatory pathways involved in the specific regulation of key functions in the kidney regulated by aldosterone
In the kidney, aldosterone regulates numerous different functions, often independently from each other, such as the control of Na+ reabsorption, K+ or H+ secretion. Moreover, pharmacological MR blockade has proven to be highly beneficial in kidney injury of various origin and in polycystic kidney disease, suggesting still unknown MR-mediated role in renal diseases. The goal of WG4 is to elucidate the signaling and molecular pathways controlling these different functions.
These studies will take advantage of a large panel of tools and techniques available among participants of WG4, from basic biochemical techniques, manipulated cell lines, electrophysiology, generation of transgenic animals, in vivo microarray and proteomics studies, and human genetics. The latter, done in families with different inherited pathological situations, will allow discovery of new genes involved in diseases, in which Na+, K+, and Ca2+ secretion are defective. The identified genes will be studied both in vitro and in vivo: in vitro, studies will use expression (or repression) systems going from Xenopus laevis oocytes, renal epithelial cell lines to cell-free systems, and analyze the role of candidate proteins by biochemical, cell biological, and electrophysiological tools; in vivo, conditional (inducible) nephron specific KO mice and other animal models will be generated. The know-how and the infrastructure to carry out studies with such animal models (from metabolic analysis of the renal parameters, blood pressure measurements by telemetry, sophisticated in vivo imaging techniques, micropuncture studies on isolated tubules) are available, as well as many transgenic models , such as mice carrying inducible nephron-specific deletion of either the MR, or the GR, or aldosterone target genes such as SGK1.
The identification of novel mineralocorticoid targets and the description of aldosterone-regulated proteins by transcriptomic and proteomic analyses performed in mineralocorticoid-sensitive renal cells
The molecular mechanisms regulating MR gene expression in the kidney will be analyzed by characterizing the post-transcriptional events involving RNA binding proteins (Tis11, HuR) that control MRNA stability and microRNAs (miRNA) after aldosterone exposure or osmotic stress.
The role of MR in kidney injury (such as ischemic or toxic stress) or in kidney diseases including diabetic nephropathy or glomerular diseases will be explored using appropriate cell and animal models. Importantly, several of the WG4 proposed participants are part of an extended Swiss research network (Kidney.ch), including most of the Swiss Universities, in which there is access to many state-of-the-art experimental techniques that will also be available also to the other COST members.
Working Group 4 members
- Olivier Staub, WG Leader,Switzerland
- Johannes Loffing, Switzerland
- Norma Bobadillo, Mexico
- John Mullins, UK
- Edith Hummler, Switzerland
- Marc Lombes, France
- Christoph Korbmacher, Germany
- Carsten Wagner, Switzerland
Several of the WG 4 participants are members of the Swiss research network The Swiss National Centre of Competence in Research (NCCR) Kidney Control of Homeostasis (Kidney.CH). The state of the art facilities will be available to other members of the ADMIRE network.
Research Group 1
Head: Dr Mark Lombes, Faculté de Médecine Paris-Sud, France
Keywords: Mineralocorticoid receptor, tissue specific action, new cellular models, transgenic animals
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Research Group 2
Head: Prof Olivier Staub, Dept of Pharmacology and Toxicology, Unviersity of Lausanne, Switzerland
Keywords: Na+ homeostasis, ion channel, protein-protein interaction, ubiquitylation, phosphorylation
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Research Group 2
Head: Prof. Dr. med. Christoph Korbmacher, Institute of Cellular and Molecular Physiology, Friedrich-Alexander-University Erlangen Nürnberg (FAU)
Keywords: Channelopathies, Ion channel regulation, ENaC, arterial hypertension, aldosterone sensitive distal nephron
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Research Group 2
Head: Professor John Mullins, Head, Molecular Physiology Unit, University/BHF Centre for Cardiovascular Science, University of Edinburgh
Keywords: Blood pressure regulation, genetics of renin-angiotensin system
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