sodium homeostasis; transport proteins; hypertension; ubiquitin; regulation; ion channels; phosphorylation; multimeric membrane protein
Rizzo Federica, Staub Olivier (2015), NEDD4-2 and salt-sensitive hypertension., in Current opinion in nephrology and hypertension
, 24(2), 111-6.
Glaudemans Bob, Terryn Sara, Gölz Nadine, Brunati Martina, Cattaneo Angela, Bachi Angela, Al-Qusairi Lama, Ziegler Urs, Staub Olivier, Rampoldi Luca, Devuyst Olivier (2014), A primary culture system of mouse thick ascending limb cells with preserved function and uromodulin processing., in Pflügers Archiv : European journal of physiology
, 466(2), 343-56.
Ronzaud Caroline, Staub Olivier (2014), Ubiquitylation and control of renal Na+ balance and blood pressure., in Physiology (Bethesda, Md.)
, 29(1), 16-26.
Lagnaz Dagmara, Arroyo Juan Pablo, Chávez-Canales María, Vázquez Norma, Rizzo Federica, Spirlí Alessia, Debonneville Anne, Staub Olivier, Gamba Gerardo (2014), WNK3 abrogates the NEDD4-2-mediated inhibition of the renal Na+-Cl- cotransporter., in American journal of physiology. Renal physiology
, 307(3), 275-86.
Rossier Bernard C, Staub Olivier, Hummler Edith (2013), Genetic dissection of sodium and potassium transport along the aldosterone-sensitive distal nephron: importance in the control of blood pressure and hypertension., in FEBS letters
, 587(13), 1929-41.
Pouly Daniel, Debonneville Anne, Ruffieux-Daidié Dorothée, Maillard Marc, Abriel Hugues, Loffing Johannes, Staub Olivier (2013), Mice carrying ubiquitin-specific protease 2 (Usp2) gene inactivation maintain normal sodium balance and blood pressure., in American journal of physiology. Renal physiology
, 305(1), 21-30.
Olivier Staub, Johannes Loffing (2013), Mineralocorticoid Action in the Aldosterone Sensitive Distal Nephron, in Robert J. Alpern (ed.), Elsevier Inc., San Diego, 1181-1211.
Ronzaud Caroline, Loffing-Cueni Dominique, Hausel Pierrette, Debonneville Anne, Malsure Sumedha Ram, Fowler-Jaeger Nicole, Boase Natasha A, Perrier Romain, Maillard Marc, Yang Baoli, Stokes John B, Koesters Robert, Kumar Sharad, Hummler Edith, Loffing Johannes, Staub Olivier (2013), Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension., in The Journal of clinical investigation
, 123(2), 657-65.
Faresse Nourdine, Debonneville Anne, Staub Olivier (2013), USP2-45 represses aldosterone mediated responses by decreasing mineralocorticoid receptor availability., in Cellular physiology and biochemistry : international journal of experimental cellular physiology, bi
, 31(2-3), 462-72.
Faresse Nourdine, Vitagliano Jean-Jacques, Staub Olivier (2012), Differential ubiquitylation of the mineralocorticoid receptor is regulated by phosphorylation., in FASEB journal : official publication of the Federation of American Societies for Experimental Biolog
, 26(10), 4373-82.
Faresse Nourdine, Lagnaz Dagmara, Debonneville Anne, Ismailji Adil, Maillard Marc, Fejes-Toth Geza, Náray-Fejes-Tóth Aniko, Staub Olivier (2012), Inducible kidney-specific Sgk1 knockout mice show a salt-losing phenotype., in American journal of physiology. Renal physiology
, 302(8), 977-85.
Rotin Daniela, Staub Olivier (2012), Nedd4-2 and the regulation of epithelial sodium transport., in Frontiers in physiology
, 3, 212-212.
Hypertension is the most common disease in the human population, affecting over 1 billion individuals worldwide, and one of the major treatable risk factors for cardiovascular diseases including stroke, myocardial infarctus, heart and kidney failure. Blood pressure is critically dependent on salt handling by the kidney. The mineralocorticoid aldosterone is the main hormone involved in the control of Na+ homeostasis. In this context, the aldosterone-sensitive distal nephron (ASDN) that includes the distal convoluted tubule (DCT), the connecting tubule (CNT), and the collecting duct (CD), precisely tunes the Na+ balance in extracellular fluids (including the blood) by regulating transepithelial Na+ transport via a number of Na+ transporting proteins, including the thiazide-sensitive Na+,Cl--cotransporter (NCC) in the DCT and the epithelial Na+ channel (ENaC) in the DCT/CNT/CD. In recent years it has become evident that aldosterone not only regulates ENaC, but also NCC in a coordinated manner. Remarkably, NCC and ENaC are differentially regulated, a phenomena referred to as the aldosterone paradox. Accordingly, if aldosterone is elevated due to hypovolemia, it stimulates primarily NCC, in order to strongly absorb Na+ without promoting K+ secretion. In contrast, if circulating aldosterone is high due to hyperkalemia, NCC activity is weak, with the purpose of providing large quantities of Na+ to the CNT/CD to stimulate electrogenic Na+ reabsorption via ENaC, serving as driving force for K+ secretion across the same cells. It is not well understood how this differential regulation is achieved. Genetic evidence suggests that a network of kinases, WNK1, WNK4, and SPAK is involved in NCC regulation, but knowledge on the precise molecular mechanisms of their action is sparse. Our recent findings, both in vitro and in vivo, suggest that Sgk1 and Nedd4-2 regulate NCC as well, adding an exciting dimension to these regulatory networks and providing some clues to the unresolved questions in the differential NCC and/or ENaC regulation. Moreover, we have identified a novel aldosterone-induced kinase, Pim3, which may also contribute to this regulatory network. We therefore postulate the following hypothesis:The thiazide-sensitive Na+,Cl--cotransporter NCC and the amiloride-sensitive Na+ channel ENaC are regulated by the ubiquitin-protein ligase Nedd4-2, which is controlled by a complex network of kinases, including the WNK/SPAK, the Sgk1, and the recently identified aldosterone-induced Pim3 kinase.Specific aims:1) To characterize, both in vitro and in vivo the molecular mechanisms of NCC regulation by Nedd4-2 and Sgk1 and their interaction with the WNK1/WNK4 /SPAK signaling pathway.2) To determine the role of the newly identified aldosterone-induced kinase Pim3 in the regulation of NCC and ENaC.Methods: Heterologous expression in Hek293 cells, oocytes and renal epithelial cells. Analysis of various KO mouse modelsExpected value of project:The project will provide novel avenues and a better understanding of the physiological/pathophysiological regulation of the thiazide-sensitive Na+,Cl--cotransporter NCC and the amiloride-sensitive epithelial Na+ channel ENaC, both fundamental for Na+ homeostasis and blood pressure regulation.