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Renal Sodium Retention in Cholestatic Mice

English title Renal Sodium Retention in Cholestatic Mice
Applicant Vogt Bruno
Number 135417
Funding scheme Project funding
Research institution Respiratory Medicine Department Universitätsklinik Inselspital
Institution of higher education University of Lausanne - LA
Main discipline Physiology : other topics
Start/End 01.07.2011 - 30.06.2014
Approved amount 256'559.20
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Keywords (7)

sodium; kidney; cirrhosis; cholestasis; ENaC; Na; K-ATPase

Lay Summary (English)

Lead
Lay summary

channel (ENaC). We developed a new model of cholestatic mice with CCD specific a+ entry of the CCD, the amiloride sensitive Na+ retention are still debated. In order to shed some light on these topics, we decided to take advantage of the transgenesis possibilities offered by the existing tissues specific knock-out (KO) mice to develop candidate gene approaches. In order to shed some light on this mechanism we decided, for the actual study, to suppress the expression of the main Na+ retention with edema and ascites formation. The renal mechanisms as well as the ions transporters involved in Na+Cirrhosis, most of it related to alcohol abuse or viral hepatitis, is a frequent and severe disease complicated by abnormal renal Na retention in cholestatic mice. Surprisingly, we observed non difference between CCD specific a+ENaC KO. These mice offer a unique opportunity to assess the role of ENaC in renal Na retention, ascites formation, or Na,K-ATPase activity. a+ENaC KO and CTL mice in term of Na transport. This question will be addressed in cholestatic and control mice with selective a+, we propose to investigate in details this new mechanism in order to identify the transporter responsible for this ENaC independent NaIn this grant proposal entering on the luminal side of the CCD act in cholestatic conditions. +new mechanism for Na that athe hypothesis transport relevant in cholestatic conditions.Based on + function, suggesting once again the existence of a new mechanism of Naindependent of ENaCENaC suppression in the CCD was confirmed by immunofluorescence. These results showed that a this unknown mechanism altering the Na,K-ATPase in the CCD, is -ENaC knockout in the CCD.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Associations of Urinary Uromodulin with Clinical Characteristics and Markers of Tubular Function in the General Population.
Pruijm M Ponte B Ackermann D Paccaud F Guessous I Ehret G Pechère-Bertschi A Vogt B Mohaupt (2016), Associations of Urinary Uromodulin with Clinical Characteristics and Markers of Tubular Function in the General Population., in Clin J Am Soc Nephrol, 11(1), 70-80.
Chronic kidney disease in the Swiss population
Vogt B (2016), Chronic kidney disease in the Swiss population, in Swiss Med Wkly, 146(14319), 1.
Diffusion tensor imaging of the human kidney: Does image registration permit scanning without respiratory triggering?
Seif M Mani LY Lu H Boesch C Reyes M Vogt B Vermathen P. (2016), Diffusion tensor imaging of the human kidney: Does image registration permit scanning without respiratory triggering?, in J Magn Reson Imaging, 44(2), 327-334.
Fibroblast growth factor 23 and markers of mineral metabolism in individuals with preserved renal function.
Dhayat NA Ackermann D Pruijm M Ponte B Ehret G Guessous I Leichtle AB Paccaud F Mohaupt M F (2016), Fibroblast growth factor 23 and markers of mineral metabolism in individuals with preserved renal function., in Kidney Int, 90(3), 648.
Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria
Dhayat N Simonin A Anderegg M Pathare G Lüscher BP Deisl C Albano G Mordasini D Hediger MA (2016), Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria, in J Am Soc Nephrol, 5, 1426-1436.
Oxidative Stress and Nuclear Factor κB (NF-κB) Increase Peritoneal Filtration and Contribute to Ascites Formation in Nephrotic Syndrome.
Udwan K Brideau G Fila M Edwards A Vogt B Doucet A. (2016), Oxidative Stress and Nuclear Factor κB (NF-κB) Increase Peritoneal Filtration and Contribute to Ascites Formation in Nephrotic Syndrome., in J Biol Chem, 291(21), 11105-11113.
Quo usque tandem abutere, Catilina, patientia nostra?
Messerli FH1 Rimoldi SF1 Vogt B2. (2016), Quo usque tandem abutere, Catilina, patientia nostra?, in Swiss Med Wkly, 146, 14344.
Relation of 24-hour urinary caffeine and caffeine metabolite excretions with
Petrovic D(1) Estoppey Younes S(1) Pruijm M(2) Ponte B(3) Ackermann D(4) (2016), Relation of 24-hour urinary caffeine and caffeine metabolite excretions with, in Nutr Metab, 13, 81.
Renal Blood Oxygenation Level-dependent Imaging in Longitudinal Follow-up of Donated and Remaining Kidneys.
Seif M Eisenberger U Binser T Thoeny HC Krauer F Rusch A Boesch C Vogt B Vermathen P. (2016), Renal Blood Oxygenation Level-dependent Imaging in Longitudinal Follow-up of Donated and Remaining Kidneys., in Radiology, 279(3), 795-804.
Sociodemographic, behavioral and genetic determinants of allostatic load in a Swiss population-based study.
Petrovic D Pivin E Ponte B Dhayat N Pruijm M Ehret G Ackermann D Guessous I Younes SE Pechè (2016), Sociodemographic, behavioral and genetic determinants of allostatic load in a Swiss population-based study., in Psychoneuroendocrinology, 67, 78-85.
The Vacuolar H+-ATPase B1 Subunit Polymorphism p.E161K Associates with Impaired Urinary Acidification in Recurrent Stone Formers.
Dhayat NA Schaller A Albano G Poindexter J Griffith C Pasch A Gallati S Vogt B Moe OW Fuste (2016), The Vacuolar H+-ATPase B1 Subunit Polymorphism p.E161K Associates with Impaired Urinary Acidification in Recurrent Stone Formers., in J Am Soc Nephrol, 5, 1426-1436.
A new technique with high reproducibility to estimate renal oxygenation using BOLD-MRI in chronic kidney disease.
Piskunowicz M Hofmann L Zuercher E Bassi I Milani B Stuber M Narkiewicz K Vogt B Burnier M (2015), A new technique with high reproducibility to estimate renal oxygenation using BOLD-MRI in chronic kidney disease., in Magn Reson Imaging, 33(3), 253-261.
Associations of ambulatory blood pressure with urinary caffeine and caffeine metabolite excretions.
Guessous I Pruijm M Ponte B Ackermann D Ehret G Ansermot N Vuistiner P Staessen J Gu Y Pacc (2015), Associations of ambulatory blood pressure with urinary caffeine and caffeine metabolite excretions., in Hypertension, 65(3), 691-696.
Copeptin is associated with kidney length, renal function, and prevalence of simple cysts in a population-based study.
Ponte B Pruijm M Ackermann D Vuistiner P Guessous I Ehret G Alwan H Youhanna S Paccaud F Mo (2015), Copeptin is associated with kidney length, renal function, and prevalence of simple cysts in a population-based study., in J Am Soc Nephrol, 6, 1415-1425.
CYP17A1 Enzyme Activity Is Linked to Ambulatory Blood Pressure in a Family-Based Population Study.
Ackermann D Pruijm M Ponte B Guessous I Ehret G Escher G Dick B Al-Alwan H Vuistiner P Pacc (2015), CYP17A1 Enzyme Activity Is Linked to Ambulatory Blood Pressure in a Family-Based Population Study., in Am J Hypertens, 4, 484-493.
ENaC activity in collecting ducts modulates NCC in cirrhotic mice.
Mordasini D Loffing-Cueni D Loffing J Beatrice R Maillard MP Hummler E Burnier M Escher G Vo (2015), ENaC activity in collecting ducts modulates NCC in cirrhotic mice., in Pflugers Arch, 467(12), 2529-2539.
Estimation of reference curves for the urinary steroid metabolome in the first year of life in healthy children: Tracing the complexity of human postnatal steroidogenesis.
Dhayat NA Frey AC Frey BM d'Uscio CH Vogt B Rousson V Dick B Flück CE. (2015), Estimation of reference curves for the urinary steroid metabolome in the first year of life in healthy children: Tracing the complexity of human postnatal steroidogenesis., in J Steroid Biochem Mol Biol, 154, 226-236.
Heritability of ambulatory and office blood pressure in the Swiss population.
Alwan H Ehret G Ponte B Pruijm M Ackermann D Guessous I Staessen JA Asayama K Kutalik Z Vui (2015), Heritability of ambulatory and office blood pressure in the Swiss population., in J Hypertens, 10, 2061-2067.
IgA-Nephropathie und Purpura Schönlein-Henoch - ein breites Spektrum.
Mani LY Huynh-Do U Vogt B Ackermann D. (2015), IgA-Nephropathie und Purpura Schönlein-Henoch - ein breites Spektrum., in Ther Umsch, 72(3), 157-160.
Inactive Matrix Gla-Protein Is Associated With Arterial Stiffness in an Adult Population-Based Study.
Pivin E Ponte B Pruijm M Ackermann D Guessous I Ehret G Liu YP Drummen NE Knapen MH Pechere (2015), Inactive Matrix Gla-Protein Is Associated With Arterial Stiffness in an Adult Population-Based Study., in Hypertension, 66(1), 85-92.
Intermittent hemodialysis treatment in cefepime-induced neurotoxicity: case report, pharmacokinetic modeling, and review of the literature.
Mani LY Kissling S Viceic D Vogt B Burnier M Buclin T Renard D. (2015), Intermittent hemodialysis treatment in cefepime-induced neurotoxicity: case report, pharmacokinetic modeling, and review of the literature., in Hemodial Int, 2, 333-343.
New insights in ACE-independent angiotensin II production.
Vogt B. (2015), New insights in ACE-independent angiotensin II production., in Exp Physiol, 100(9), 992.
Patient safety in vascular access patients on hemodialysis: contrast agents and renal function.
Vogt B. (2015), Patient safety in vascular access patients on hemodialysis: contrast agents and renal function., in Contrib Nephrol, 184, 51-58.
Pharmacokinetic modelling of dialytic clearance in a case of acyclovir intoxication.
Kissling S Fuchs A Gobin N Vogt B Burnier M Decosterd LA Buclin T Livio F. (2015), Pharmacokinetic modelling of dialytic clearance in a case of acyclovir intoxication., in Int J Antimicrob Agents, 45(3), 325-327.
The role of rituximab in the treatment of ANCA-associated vasculitides (AAV).
Daikeler T Kistler AD Martin PY Vogt B Huynh-Do U. (2015), The role of rituximab in the treatment of ANCA-associated vasculitides (AAV)., in Swiss Med Wkly, 145, 14103.
Urine Fetuin-A is a biomarker of autosomal dominant polycystic kidney disease progression.
Piazzon N Bernet F Guihard L Leonhard WN Urfer S Firsov D Chehade H Vogt B Piergiovanni S P (2015), Urine Fetuin-A is a biomarker of autosomal dominant polycystic kidney disease progression., in J Transl Med, 13, 103.
[Electrolyte disorders in preeclampsia. A case report].
Bodenmann Gobin P Gobin N Ducry J Portmann L Vial Y Vogt B (2014), [Electrolyte disorders in preeclampsia. A case report]., Nephrol Ther. 2014 Feb;10(1):51-7, Genève.
Determinants of renal tissue oxygenation as measured with BOLD-MRI in chronic kidney disease and hypertension in humans.
Pruijm M Hofmann L Piskunowicz M Muller ME Zweiacker C Bassi I Vogt B Stuber M Burnier M (2014), Determinants of renal tissue oxygenation as measured with BOLD-MRI in chronic kidney disease and hypertension in humans., in PLoS One, 23(9), e95895-e95895.
Effect of Cyp27A1 gene dosage on atherosclerosis development in ApoE-knockout mice
Zurkinden L Solcà C Vögeli IA Vogt B Ackermann D Erickson SK Frey FJ Sviridov D Escher G (2014), Effect of Cyp27A1 gene dosage on atherosclerosis development in ApoE-knockout mice, in FASEB J, 28(3), 1198-1209.
Epidemiology of masked and white-coat hypertension: the family-based SKIPOGH study.
Alwan H Pruijm M Ponte B Ackermann D Guessous I Ehret G Staessen JA Asayama K Vuistiner P Y (2014), Epidemiology of masked and white-coat hypertension: the family-based SKIPOGH study., in PLoS One., 24(3), e92522-e92522.
Intermittent hemodialysis treatment in cefepime-induced neurotoxicity: Case report, pharmacokinetic modeling, and review of the literature.
Mani LY Kissling S Viceic D Vogt B Burnier M Buclin T Renard D (2014), Intermittent hemodialysis treatment in cefepime-induced neurotoxicity: Case report, pharmacokinetic modeling, and review of the literature., in Hemodial Int., 2, 333-343.
Local renal circadian clocks control fluid-electrolyte homeostasis and BP
Tokonami N Mordasini D Pradervand S Centeno G Jouffe C Maillard M Bonny O Gachon F Gomez RA (2014), Local renal circadian clocks control fluid-electrolyte homeostasis and BP, in J Am Soc Nephrol, 25(7), 1430-1439.
Reference values and factors associated with renal resistive index in a family-based population study.
Ponte B Pruijm M Ackermann D Vuistiner P Eisenberger U Guessous I Rousson V Mohaupt MG Alwan (2014), Reference values and factors associated with renal resistive index in a family-based population study., in Hypertension, 63(1), 136-142.
Regulation of 11β-Hydroxysteroid Dehydrogenase Type 2 by MicroRNA.
Rezaei M Andrieu T Neuenschwander S Bruggmann R Mordasini D Frey FJ Vogt B Frey BM (2014), Regulation of 11β-Hydroxysteroid Dehydrogenase Type 2 by MicroRNA., in Hypertension, 64(4), 860-866.
[Kidney and smoking: literature review and focus].
Phan O El Housseini Y Burnier M Vogt B. (2013), [Kidney and smoking: literature review and focus]., in Ther Umsch, 9(2), 67-72.
Blockade of the renin-angiotensin system and renal tissue oxygenation as measured with BOLD-MRI in patients with type 2 diabetes.
Pruijm M Hofmann L Zanchi A Maillard M Forni V Muller ME Wuerzner G Vogt B Stuber M Burnier (2013), Blockade of the renin-angiotensin system and renal tissue oxygenation as measured with BOLD-MRI in patients with type 2 diabetes., in Diabetes Res Clin Pract, 99(2), 136-144.
Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression.
Trudu M1 Janas S Lanzani C Debaix H Schaeffer C Ikehata M Citterio L Demaretz S Trevisani F (2013), Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression., in Nat Med, 19(12), 1655-1660.
Effect of dark chocolate on renal tissue oxygenation as measured by BOLD-MRI in healthy volunteers.
Pruijm M Hofmann L Charollais-Thoenig J Forni V Maillard M Coristine A Stuber M Burnier M Vo (2013), Effect of dark chocolate on renal tissue oxygenation as measured by BOLD-MRI in healthy volunteers., in Clin Nephrol, 80(3), 211-217.
Renal tissue oxygenation in essential hypertension and chronic kidney disease.
Pruijm M Hofmann L Vogt B Muller ME Piskunowicz M Stuber M Burnier M. (2013), Renal tissue oxygenation in essential hypertension and chronic kidney disease., in Int J Hypertens, 2013, 696598.
α-Ketoglutarate regulates acid-base balance through an intrarenal paracrine mechanism
Tokonami N1 Morla L Centeno G Mordasini D Ramakrishnan SK Nikolaeva S Wagner CA Bonny O Houi (2013), α-Ketoglutarate regulates acid-base balance through an intrarenal paracrine mechanism, in J Clin Invest, 123(7), 3166-3171.
[Hypertension therapy in patients with renal artery stenosis].
Vogt B Maillard M Burnier M (2012), [Hypertension therapy in patients with renal artery stenosis]., in Ther Umsch, 69(5), 279-281.
[New european guidelines for dyslipidemia].
Riesen WF Virgini V Vogt B Rodondi N. (2012), [New european guidelines for dyslipidemia]., in Rev Med Suisse, 8(331), 525-530.
[What reasonable applications for regional citrate anticoagulation in renal replacement therapy?].
Kissling S Wilson P Ridel C Burnier M Vogt B. (2012), [What reasonable applications for regional citrate anticoagulation in renal replacement therapy?]., in Rev Med Suisse, 8(330), 452-456.
Renal perfusion evaluation with contrast-enhanced ultrasonography.
Schneider AG Hofmann L Wuerzner G Glatz N Maillard M Meuwly JY Eggimann P Burnier M Vogt B (2012), Renal perfusion evaluation with contrast-enhanced ultrasonography., in Nephrol Dial Transplant, 27(2), 674-681.
[New radiological techniques to investigate patients suffering from chronic kidney disease].
Pruijm M Ponte B Hofmann L Vogt B Eisenberger U Meuwly JY Burnier M (2011), [New radiological techniques to investigate patients suffering from chronic kidney disease]., in Rev med Suisse, 7(284), 505-509.
[Rationale and clinical evidence for the use of rituximab in glomerular diseases].
Mani LY Vogt B Burnier M Golshayan D. (2011), [Rationale and clinical evidence for the use of rituximab in glomerular diseases]., in Rew Med Suisse, 13(7), 819-824.
Androgen biosynthesis during minipuberty favors the backdoor pathway over the classic pathway: Insights into enzyme activities and steroid fluxes in healthy infants during the first year of life from
Dhayat NA Dick B Frey BM d'Uscio CH Vogt B Flück CE., Androgen biosynthesis during minipuberty favors the backdoor pathway over the classic pathway: Insights into enzyme activities and steroid fluxes in healthy infants during the first year of life from, in J Steroid Biochem Mol Biol.
Reduction of cortical oxygenation in chronic kidney disease: evidence obtained with a new analysis method of blood oxygenation level-dependent magnetic resonance imaging.
Milani B12 Ansaloni A1 Sousa-Guimaraes S1 Vakilzadeh N1 Piskunowicz M3 Vogt B4 Stuber M25 B, Reduction of cortical oxygenation in chronic kidney disease: evidence obtained with a new analysis method of blood oxygenation level-dependent magnetic resonance imaging., in Nephrol Dial Transplant.

Collaboration

Group / person Country
Types of collaboration
Prof. D. Firsov, Pharmacologie et Toxicologie, UniL, Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Endocrinology Prof Brian Walker Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
University of Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
University of Paris Les Cordeliers, Laboratoire de Physiologie Rénale, Prof. A. Doucet France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Endocrinolgy Prof. Christa Flück Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Franco-Suisse meeting 2015 Talk given at a conference Some Good Reasons to Measure Blood Pressure in CYP27A1 KO Mice 26.03.2015 Paris, France Vogt Bruno; Mordasini David;
ERA-EDTA Talk given at a conference WHAT IS THE ROLE OF ENaC IN THE Na+ RETENTION 18.05.2013 Istanbul, Turkey Vogt Bruno; Mordasini David;
Renal Physiology: Paris meets Lausanne. Talk given at a conference Renal sodium retention in cholestatic mice 26.04.2012 CHUV, Lausanne, Switzerland Vogt Bruno; Mordasini David;
Swiss Society of Nephrology meeting 2011 Montreux Talk given at a conference Role of ENaC in renal soidum retenion in cholestatic mice 30.11.2011 Montreux, Switzerland, Switzerland Vogt Bruno; Mordasini David;


Self-organised

Title Date Place
Franco-suisse meeting 23.03.2016 Bern, Switzerland
Steroid meeting 04.02.2016 Bern, Switzerland
Symposium on renal sodium retention 14.06.2012 CHUV and University ofLausanne, Switzerland

Associated projects

Number Title Start Funding scheme
157759 Steroid Analysis by GCxGC MS TOF (Mass Spectrometry Time-of-flight) 01.12.2014 R'EQUIP
120406 Renal sodium retention in cholestatic mice 01.04.2008 Project funding

Abstract

Cirrhosis, most of it related to alcohol abuse or viral hepatitis, is a frequent and severe disease complicated by abnormal renal Na+ retention with edema and ascites formation. The renal mechanisms as well as the ions transporters involved in Na+ retention are still debated. In order to shed some light on these topics, we decided to take advantage of the transgenesis possibilities offered by the existing tissues specific knock-out (KO) mice to develop candidate gene approaches. In our first previous study, we transposed successfully the well known bile duct ligation (BDL) induced cirrhosis model into mice. Our results showed that BDL induced cirrhotic mice compared to sham-operated animals had an increased renal Na+ retention and an increased Na,K-ATPase activity in the cortical collecting duct (CCD) exclusively, independently of corticoids stimulation. These results suggested that an unknown, “adrenal independent” and CCD specific mechanism is altering the Na,K-ATPase activity in decompensate cirrhosis. In order to shed some light on this mechanism we decided, for the actual study, to suppress the expression of the main Na+ entry of the CCD, the amiloride sensitive Na+ channel (ENaC). We developed a new model of cholestatic mice with CCD specific ?ENaC KO. These mice offer a unique opportunity to assess the role of ENaC in renal Na+ retention in cholestatic mice. Surprisingly, we observed non difference between CCD specific ?ENaC KO and CTL mice in term of Na+ retention, ascites formation, or Na,K-ATPase activity. ?ENaC suppression in the CCD was confirmed by immunofluorescence. These results showed that a this unknown mechanism altering the Na,K-ATPase in the CCD, is independent of ENaC function, suggesting once again the existence of a new mechanism of Na+ transport relevant in cholestatic conditions.Based on the hypothesis that a new mechanism for Na+ entering on the luminal side of the CCD act in cholestatic conditions. In this grant proposal, I propose to investigate in details this new mechanism in order to identify the transporter responsible for this ENaC independent Na+ transport. This question will be addressed in cholestatic and control mice with selective ?-ENaC knockout in the CCD by: 1.Metabolic analysis of the bile duct ligated induced cirrhosis mouse model2.Measurement of the Na,K-ATPase activity in the CCD of BDL induced cirrhotic mice in preascitic stage 3.Analyzing the influence of Na+ intake on Na,K-ATPase activity in the CCD of CCD specific ?ENac KO mice4.Analyses of the Na+-dependent Cl-/HCO3- exchanger and the pendrin, described recently, as a candidate mechanism by in vitro microperfusion, in collaboration with the Dr. A. Doucet’s lab in Paris.5.Transcriptomic analysis by microarray of the whole kidney and COPAS sorted CCD from BDL induced cirrhotic mice, in collaboration with the Lausanne DNA array Facility6.Kidney immunohistochemistry of candidate genes, in collaboration with Prof. J. Loffing in ZurichThe identification of new mechanism(s) for Na+ entering on the luminal side of the CCD and/or new mechanism(s) for activation of Na,K-ATPase activity on the basolateral side in cholestatic conditions, will provide important new insights on aldosterone independent and adrenal independent regulation of Na+ transport in the CCD in cholestatic cirrhosis and in general physiology and pathophysiology.
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