Adaptive physiological water conservation explains hypertension and muscle catabolism in experimental chronic renal failure

• Type of Material: Article
• Authors: Johannes Kovarik, Duke‐NUS Medical School; Norihiko Morisawa, Kagawa University; Johannes Wild, Johannes Gutenberg University of Mainz; Adriana Marton, Duke‐NUS Medical School; Kaooru Takase-Minegishi, Duke‐NUS Medical School; Shintaro Minegishi, Duke‐NUS Medical School; Steffen Daub, Johannes Gutenberg University of Mainz; Jeff Sands, Emory University; Janet Klein, Emory University; James Bailey, Emory University; Jean-Paul Kovalik, Duke‐NUS Medical School; Manfred Rauh, Research Laboratory; Susanne Karbach, Johannes Gutenberg University of Mainz; Karl Hilgers, University Clinic Erlangen; Friedrich Luft, Max Delbrück Center for Molecular Medicine; Akira Nishiyama, Kagawa University; Daisuke Nakano, Kagawa University; Kento Kitada, Duke‐NUS Medical School; Jens Titze, Duke‐NUS Medical School
• Language: English
• Date: 2021-03-07
• Publisher: WILEY
• Publication Version: Final Published Version
• Copyright Statement: © 2021 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1111/apha.13629
• Title of Journal or Parent Work: ACTA PHYSIOLOGICA
• Volume: 232
• Issue: 1
• Start Page: e13629
• End Page: e13629
• Grant/Funding Information: JT was supported by grants from the German Federal Ministry for Economics and Technology/DLR Forschung unter Weltraumbedingungen (Mars500‐III; 50WB2024), the NIH (RO1 HL118579), the Renal Research Institute, and by funding from National Medical Research Council (NMRC) of Singapore to the Duke‐NUS Medical School.; KK was supported by an Overseas Fellowship the Japan Society for the Promotion of Science; JJK by the Erwin Schrödinger Program of the FWF Austrian Science Funds (J3961‐B30); KTM by the Japan Society for the Promotion of Science (19K17889), the Astellas Foundation for Research on Metabolic Disorders, the Mitsukoshi Health and Welfare Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Uehara Memorial Foundation; and SM by the Public Trust Cardiovascular Research Fund and the Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad Fund. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Keywords: INCREASED UREA SYNTHESIS; SALINITY ADAPTATION; Physiology; ELECTROLYTE HOMEOSTASIS; organic osmolytes; shuttle; Science & Technology; urea cycle; muscle mass loss; ESTIVATING AFRICAN LUNGFISH; transamination; liver; PROTOPTERUS-ANNECTENS; aestivation; Life Sciences & Biomedicine; hepato‐ NITROGEN-METABOLISM; transepidermal water loss; XENOPUS-LAEVIS; alanine‐ dehydration; OSMOTIC REGULATION; body water; urine concentration; purine metabolism; SKIN BLOOD-FLOW; hypertension; MOLECULAR CHARACTERIZATION; barrier concept; double‐ glucose‐ kidney; renal; body sodium; skin; glycine methylation
• Research Categories: Health Sciences, Pharmacology

Abstract

Aim: We have reported earlier that a high salt intake triggered an aestivation-like natriuretic-ureotelic body water conservation response that lowered muscle mass and increased blood pressure. Here, we tested the hypothesis that a similar adaptive water conservation response occurs in experimental chronic renal failure. Methods: In four subsequent experiments in Sprague Dawley rats, we used surgical 5/6 renal mass reduction (5/6 Nx) to induce chronic renal failure. We studied solute and water excretion in 24-hour metabolic cage experiments, chronic blood pressure by radiotelemetry, chronic metabolic adjustment in liver and skeletal muscle by metabolomics and selected enzyme activity measurements, body Na+, K+ and water by dry ashing, and acute transepidermal water loss in conjunction with skin blood flow and intra-arterial blood pressure. Results: 5/6 Nx rats were polyuric, because their kidneys could not sufficiently concentrate the urine. Physiological adaptation to this renal water loss included mobilization of nitrogen and energy from muscle for organic osmolyte production, elevated norepinephrine and copeptin levels with reduced skin blood flow, which by means of compensation reduced their transepidermal water loss. This complex physiologic-metabolic adjustment across multiple organs allowed the rats to stabilize their body water content despite persisting renal water loss, albeit at the expense of hypertension and catabolic mobilization of muscle protein. Conclusion: Physiological adaptation to body water loss, termed aestivation, is an evolutionary conserved survival strategy and an under-studied research area in medical physiology, which besides hypertension and muscle mass loss in chronic renal failure may explain many otherwise unexplainable phenomena in medicine.