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

高盐饮食在西方社会是常态。它已被证明与血管功能障碍、高血压和增加心血管死亡率和发病率有关。虽然这是一个广为人知的事实，但高盐饮食与内皮功能障碍、胰岛素抵抗、血管僵硬、代谢综合征、减轻血压下降和炎症增加之间的联系背后的机制仍不完全清楚。传统上，一个多世纪前克劳德·伯纳德提出的环境，创造了我们对体内钠稳态的理解。这个模型包含了细胞外电解质和水含量之间的平衡。最近，Jens Tize和他的同事们能够彻底改变我们对钠稳态的理解，表明细胞外钠在储存时没有随后的水分保持，这是在喂食高盐饮食的动物中观察到的现象。细胞外钠的增加导致一种名为TONEBP的转录因子的激活，该转录因子能够将过量的间质钠转化为(病理)生理反应。然而，目前还不清楚哪些基因和蛋白质在这种翻译中发挥了作用。由于CD40配体在T细胞和B细胞之间的相互作用、动脉粥样硬化斑块的形成及其免疫系统细胞的侵袭中起着至关重要的作用，在矽肺中，属于CD40配体的基因序列是上述转录因子TONEBP的靶标。因此，高盐饮食动物的(病理)生理效应很可能是由于TONEBP和CD40配体启动子区域的相互作用。在这项研究中，我想从三个方面评估缺乏CD40配体的小鼠的这种相互作用：1.CD40L-/-小鼠在高盐饮食的同时接受TNP-KHL免疫时，免疫球蛋白产生减少。2.CD40L-/-小鼠皮肤毛细淋巴管密度降低，导致高盐饮食时Na+清除障碍。3.喂饲高盐饲料的CD40L-/-小鼠在间质中积累的渗透失活Na+与野生型小鼠相当或更多，从而导致TONEBP活性增加。虽然这会导致如上所述的野生型动物的内皮功能障碍，但CD40L缺陷将保护动物免受转录因子的有害影响，从而使内皮功能不受损害。

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.