Dietary K+ and Na+, renal function and blood pressure control
The kidneys are central for blood pressure control. Arterial hypertension is cause and consequence of kidney disease. Dietary habits (e.g. high sodium (Na+), low potassium (K+) intakes), impaired hormonal signaling and genetic predisposition are thought to contribute significantly to the pathogenesis of hypertension. The main objective of this WP is to elucidate the mechanism by which dietary K+ and Na+ impacts on the normal and diseased kidney and which factors determine the individual K+ and Na+ sensitivity of blood pressure.
Renal impact of dietary K+
High K+ intake has antihypertensive effects. The kidneys respond very quickly to dietary K+ intake, e.g. after eating a banana. Using various ex vivo assays (e.g. kidney slice preparations, isolated-perfused kidney) and genetically modified mouse models, we aim to better understand the beneficial effects of dietary K+ and to identify novel signaling pathways involved in renal blood pressure control.
- Penton D, Czogalla J, Loffing J. Dietary potassium and the renal control of salt balance and blood pressure. Pflugers Arch. 467: 513-30 (2015)
- Sorensen MV, Grossmann S, Roesinger M, Gresko N, Todkar AP, Barmettler G, Ziegler U, Odermatt A, Loffing-Cueni D, Loffing J. Rapid dephosphorylation of the renal sodium chloride cotransporter in response to oral potassium intake in mice. Kidney Int. 83: 811-24 (2013)
Candidate genes for renal K+ response
The underlying genetic determinants of the K+ sensitivity of blood pressure are largely unknown. Using genetic analysis, we identified several candidate genes for the renal control of K+ homeostasis. Using mainly mouse models and heterologous expression systems, the project characterizes the functional role of these candidate genes and tests their contribution to the K+ sensitivity of blood pressure.
- Keppner A, Marc D, Sergi C, Ansermet, C, De Bellis D, Kratschmar DV, Canonica J, Klusonova P, Fenton RA, Odermatt A, Crambert G, Hoogewijs D, Hummler E. Deletion of the serine protease CAP2/Tmprss4 leads to dysregulated renal water handling upon dietary potassium depletion. Scientific Reports 9: 19540 (2019)
- Canonica J, Frateschi S, Boscardin E, Ebering A, Sergi C, Jäger Y, Peyrollaz T, Mérillat AM, Maillard M, Klusonova P, Odermatt A, Koesters R, Debonneville A, Staub O, Verouti SN, Hummler E. Lack of renal tubular glucocorticoid receptor decreases the thiazide-sensitive Na+/Cl- cotransporter NCC and transiently affects sodium handling. Frontiers Physiology 10: 989 (2019)
Combined effects of dietary Na+ & K+
The intake of Na+ and K+ varies in wide ranges and independent from each other. Nevertheless, the renal handling of both ions largely interferes. The aim of this project is to analyze the combined effects of differently modulated dietary Na+ and K+ intake on body fluid and ion homeostasis and to address its impact on the control of blood pressure and the propensity for urinary stone formation. Underlying mechanism are addressed for both the healthy and the diseased kidney.
- Udwan D, Abed A, Roth I, Dizin E, Maillard M, Bettoni C, Loffing J, Wagner C, Edwards A, Feraille E. Dietary sodium induces a redistribution of the tubular
metabolic workload. J Physiol 595:1-18 (2017)
- Wang Y, Leroy V, Maunsbach A, Doucet A, Hasler U, Dizin E, Ernandez T, de Seigneux S, Martin P, Féraille E. Sodium Transport Is Modulated by p38 Kinase–Dependent Cross-Talk between ENaC and Na,K-ATPase in Collecting Duct Principal Cells. J Am Soc Nephrol. 25: 250-59 (2014)
Adrenal gland, K+ & hypertension
The adrenal gland and the kidney cooperate for the control of K+ and Na+ homeostasis and blood pressure. The objective of this projects is to elucidate the mechanisms that mediate the effects of dietary and extracellular K+ on adrenal aldosterone secretion and to address its consequences on ion homeostasis, blood pressure and general health. To address these questions, we analyze data on human patient cohorts and perform experiments on mouse models with altered adrenal gland function.
- Swierczynska MN, Betz MJ, Colombi M, Dazert E, Jenö P, Moes S, Pfaff C, Glatz K, Reincke M, Beuschlein F, Donath MY, Hall MN. Proteomic Landscape of Aldosterone-Producing Adenoma. Hypertension 73: 469-80 (2019)
- Murakami M, Rhayem Y, Kunzke T, Sun N, Feuchtinger A, Ludwig P, Strom TM, Knösel T, Kirchner T, Williams TA, Reincke M, Walch AK, Beuschlein F. High Throughput in situ Metabolomics for Genotype/phenotype Correlation in Aldosterone-Producing Adenomas. JCI Insight (2019), in press