The Effects of CD40 Ligand Deficiency on Vascular Dysfunction, Immunoglobulin Production and Lymph Capillary Density in a Murine Model for High-Salt Diet

• Applicant: Dr. Steffen Daub
• Subject Area: Cardiology, Angiology ; Nutritional Sciences
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 290587856

• Final Report Year: 2018

Final Report Abstract

High salt intake is generally assumed to lead to increased thirst and subsequent water intake. If the water were to be replaced by high-caloric beverages, such as soda, this is regarded as contributing to the so-called obesity epidemic that spreads throughout western society. In searching for more detailed effects of salt intake on the metabolism and vascular function of humans and mice, our group has found new water-conserving mechanisms that completely challenge this established concept providing a link between energy homeostasis and water-conservation. Increased salt intake, naturally, leads to reduced aldosterone levels, while at the same time increasing cortisol levels in men and mice. In total, this leads to reduced, not increased water intake. This is achieved by inducing intricate water-conserving mechanisms that comprise the concentration of the urine in the kidney by the endogenous osmolyte urea. In order to generate the amount of urea necessary to prevent water loss, a concerted effort by liver, muscle and kidney is required, that needs food-derived nutrients in order enable the liver to maintain urea generation. When ingesting a high-salt diet, mice show a greatly increased demand for nutrients that is normally met by increasing food intake in order to fuel the mechanism described above. Incapability to meet this demand immediately results in an emergency metabolic state that comprises the activation of enzymes that detect a lack of energy within muscle tissue. A process termed autophagy then ensures muscle mass is reduced by the ensuing hypercortisolaemia as well as a lack of foodderived energy, which ultimately results in the flux of muscle-derived amino acids to the liver, where they can be effectively catabolized into the much-needed urea. Astonishingly, while a high-salt diet is regarded as a key contributor to the development of arterial hypertension, we could show that our mice ingesting an increased amount of salt actually did not develop arterial hypertension in the long run. After a short increase in response to a high-salt diet, blood pressure normalizes in these mice, while their heart rate is reduced below the one observed in the control group. In concert with reduced locomotor activity, we interpret this finding as an additional mechanism in order to conserve energy and thus the ability to retain water. G. Kolata: “Why everything we know about salt may be wrong”. New York Times. May 8, 2017

Publications

• High salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation. J. J Clin Invest. 2017 May 1
  Kitada K, Daub S, Zhang Y, Klein JD, Nakano D, Pedchenko T, Lantier L, LaRocque LM, Marton A, Neubert P, Schröder A, Rakova N, Jantsch J, Dikalova AE, Dikalov SI, Harrison DG, Müller DN, Nishiyama A, Rauh M, Harris RC, Luft FC, Wassermann DH, Sands JM, Titze J
  
• Increased salt consumption induces body water conservation and decreases fluid intake. J Clin Invest. 2017 May 1
  Rakova N, Kitada K, Lerchl K, Dahlmann A, Birukov A, Daub S, Kopp C, Pedchenko T, Zhang Y, Beck L, Johannes B, Marton A, Müller DN, Rauh M, Luft FC, Titze J
  
• Renal physiology: Burning calories to excrete salt. Nat Rev Nephrol. 2017 Jun
  Rabelink TJ