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

A high-salt diet is the norm in Western society. It has been shown to be associated with vascular dysfunction, hypertension and increased cardiovascular mortality and morbidity. While this is a widely known and well-proven fact, the mechanism behind the association between high-salt diet and endothelial dysfunction, insulin resisistance, vascular stiffness, metabolic syndrome, attenuated blood pressure dipping and increased inflammation remains incompletely understood. Traditionally, the milieu intérieur, as proposed by Claude Bernard over a century ago, has coined our unterstanding of sodium homeostasis within the body. This model envolves an equilibrium between extracellular electrolyte and water content. Recently, Jens Titze and colleagues were able to revolutionize our understanding of sodium homeostasis, showing that extracellular Sodium is being stored without subsequent water retention, a phenomenon observed in animals fed a high-salt diet. An increase in extracellular Sodium has been shown to lead to the activation of a transcription factor named TonEBP, which is able to translate an excess of interstitial sodium into a (patho-)physiological response. It is of yet unclear, however, which genes and proteins play a part in this translation. With the CD40 Ligand being crucial to the interaction between T cells and B cells, the formation of atherosclerotic plaques and their invasion by cells of the immune system, in silico the gene-sequence belonging to CD40 Ligand is a target for the aforementioned transcription factor TonEBP. Therefore it is highly likely that the (patho-)physiological effects in animals fed a high-salt diet are due to the interaction between TonEBP and the promotor region of CD40 Ligand.In this study, I would like to assess this Interaction in mice lacking CD40 Ligand in three ways: 1. CD40L-/- mice will show impaired immunoglobulin production when subjected to TNP-KHL immunization while fed a high-salt diet. 2. CD40L-/- mice will display reduced lymph capillary density in skin, resulting in impaired Na+ clearance when fed a high-salt diet. 3. CD40L-/- mice fed a high-salt diet will accumulate as much or more osmotically inactive Na+ in the interstitium than their wild-type littermates, thus resulting in an increase in TonEBP activity. While this will cause endothelial dysfunction in wild type animals as mentioned above, CD40L-deficiency will protect the animals from the harmful effects of the transcription factor, thus rendering endothelial function unimpaired.

• DFG Programme: Research Fellowships
• International Connection: USA
• Hosts: Professor Dr. David Harrison; Professor Dr. Jens Marc Titze