Johannes Wild1,2, Rebecca Jung1, Tanja Knopp1, Panagiotis Efentakis1,3, Dimitra Benaki3, Alexandra Grill1, Joanna Wegner4, Michael Molitor1,2, Venkata Garlapati1, Natalia Rakova5, Lajos Markó6, Adriana Marton7, Emmanuel Mikros3, Thomas Münzel2, Sabine Kossmann8, Manfred Rauh9, Daisuke Nakano10, Kento Kitada7,10, Friedrich Luft6, Ari Waisman11, Philip Wenzel1,2, Jens Titze5,7,12, Susanne Karbach1,2. 1. Center for Thrombosis and Hemostasis (CTH), Johannes Gutenberg-University Mainz, Mainz, Germany. 2. Center for Cardiology, Cardiology I, Johannes Gutenberg-University Mainz, Mainz, Germany. 3. Faculty of Pharmacy, University of Athens, Panepistimiopolis of Zographou, Athens, Greece. 4. Department of Dermatology, Johannes Gutenberg-University Mainz, Mainz, Germany. 5. Division of Nephrology and Hypertension, University Clinic Erlangen, Erlangen, Germany. 6. Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine, Berlin, Germany. 7. Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore. 8. Heart Research Institute Sydney, Sydney, Australia. 9. Research Laboratory, Division of Paediatrics, University Clinic Erlangen, Erlangen, Germany. 10. Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa, Japan. 11. Institute for Molecular Medicine, University Medical Center of Mainz, Mainz, Germany. 12. Division of Nephrology, Duke University School of Medicine, Durham, NC, USA.
Abstract
AIM: Recent evidence suggests that arterial hypertension could be alternatively explained as a physiological adaptation response to water shortage, termed aestivation, which relies on complex multi-organ metabolic adjustments to prevent dehydration. Here, we tested the hypothesis that chronic water loss across diseased skin leads to similar adaptive water conservation responses as observed in experimental renal failure or high salt diet. METHODS: We studied mice with keratinocyte-specific overexpression of IL-17A which develop severe psoriasis-like skin disease. We measured transepidermal water loss and solute and water excretion in the urine. We quantified glomerular filtration rate (GFR) by intravital microscopy, and energy and nitrogen pathways by metabolomics. We measured skin blood flow and transepidermal water loss (TEWL) in conjunction with renal resistive indices and arterial blood pressure. RESULTS: Psoriatic animals lost large amounts of water across their defective cutaneous epithelial barrier. Metabolic adaptive water conservation included mobilization of nitrogen and energy from muscle to increase organic osmolyte production, solute-driven maximal anti-diuresis at normal GFR, increased metanephrine and angiotensin 2 levels, and cutaneous vasoconstriction to limit TEWL. Heat exposure led to cutaneous vasodilation and blood pressure normalization without parallel changes in renal resistive index, albeit at the expense of further increased TEWL. CONCLUSION: Severe cutaneous water loss predisposes psoriatic mice to lethal dehydration. In response to this dehydration stress, the mice activate aestivation-like water conservation motifs to maintain their body hydration status. The circulatory water conservation response explains their arterial hypertension. The nitrogen-dependency of the metabolic water conservation response explains their catabolic muscle wasting.
AIM: Recent evidence suggests that arterial hypertension could be alternatively explained as a physiological adaptation response to water shortage, termed aestivation, which relies on complex multi-organ metabolic adjustments to prevent dehydration. Here, we tested the hypothesis that chronic water loss across diseased skin leads to similar adaptive water conservation responses as observed in experimental renal failure or high salt diet. METHODS: We studied mice with keratinocyte-specific overexpression of IL-17A which develop severe psoriasis-like skin disease. We measured transepidermal water loss and solute and water excretion in the urine. We quantified glomerular filtration rate (GFR) by intravital microscopy, and energy and nitrogen pathways by metabolomics. We measured skin blood flow and transepidermal water loss (TEWL) in conjunction with renal resistive indices and arterial blood pressure. RESULTS: Psoriatic animals lost large amounts of water across their defective cutaneous epithelial barrier. Metabolic adaptive water conservation included mobilization of nitrogen and energy from muscle to increase organic osmolyte production, solute-driven maximal anti-diuresis at normal GFR, increased metanephrine and angiotensin 2 levels, and cutaneous vasoconstriction to limit TEWL. Heat exposure led to cutaneous vasodilation and blood pressure normalization without parallel changes in renal resistive index, albeit at the expense of further increased TEWL. CONCLUSION: Severe cutaneous water loss predisposes psoriatic mice to lethal dehydration. In response to this dehydration stress, the mice activate aestivation-like water conservation motifs to maintain their body hydration status. The circulatory water conservation response explains their arterial hypertension. The nitrogen-dependency of the metabolic water conservation response explains their catabolic muscle wasting.
Authors: Tanja Knopp; Tabea Bieler; Rebecca Jung; Julia Ringen; Michael Molitor; Annika Jurda; Thomas Münzel; Ari Waisman; Philip Wenzel; Susanne Helena Karbach; Johannes Wild Journal: Nutrients Date: 2021-05-31 Impact factor: 5.717
Authors: Sandra Nihlén; Robert Frithiof; Jens Titze; Rafael Kawati; Johan Rasmusson; Christian Rylander; Andreas Pikwer; Markus Castegren; Anton Belin; Michael Hultström; Miklos Lipcsey Journal: Function (Oxf) Date: 2021-10-29