Novel driving forces for water transport & osmoregulation: carbonate precipitation and osmotic coefficients

脊椎动物，包括人类，大约70%是由水组成的。平衡水的摄入和输出显然对健康至关重要，但大多数人都没有意识到水在他们体内一直进行着巨大的内部运动。例如，肾脏，肠道和胰腺每天集体运输8倍于我们身体总水量的水分进出这些组织。因此，了解这些器官使用的机制以及它们的细胞（称为上皮细胞）如何运作这种水运输是很重要的。尽管如此重要，水运机制仍然是许多辩论的主题。尽管如此，50多年来人们已经理解，水的净输送需要盐（特别是氯化钠或NaCl）首先在一个特定方向上输送，然后通过称为渗透的过程在同一方向上驱动流体输送（其次）。尽管这一共识，水运输的确切路线，通过上皮细胞是激烈的争议。例如，它是否通过称为水通道蛋白的特殊蛋白质穿过细胞膜？还是在细胞间挤压本提案的新奇在于发现了两种新的影响水运的机制，这两种机制在概念上与当前辩论的其他领域非常不同。这些想法挑战了既定的教条，不依赖于盐以与水相同的方向运输，代表了我们理解的根本变化，并为动物上皮细胞中的水运输机制提供了新的模型。这一发现是通过研究海洋鱼类如何饮用海水并通过肠道处理这种液体以避免脱水而得出的。就像人类饮用普通液体一样，这些动物首先将NaCl从肠道输送到血液中，然后通过渗透作用将水输送到血液中。然而，海洋鱼类还有另一个锦囊妙计，可以最大限度地提高它们的水提取能力。它们分泌一种不同的化合物，称为碳酸氢盐（与小苏打中发现的相同）进入肠道，与水吸收相反。这会在吞下的海水中引起化学反应，导致海水中含有的高水平钙沉淀为固体，白色碳酸钙团块（如石灰石）。这些“肠道岩石”最终会被排出体外，但对鱼的好处是减少了肠道液体中溶解的总化合物，这反过来又使水更容易提取到血液中。我们建议通过使用3种不同的海洋鱼类（比目鱼，罗非鱼和鳟鱼）来进一步研究这种新的过程，这些鱼类产生的碳酸氢盐数量非常不同，因此预计具有不同的吸水效率。低温和高压也会抑制降水，因此我们将比较低温和高压（在气压室中）下鱼的吸水率。碳酸盐沉淀发生在人类疾病中，如肾结石和胰腺结石，因此研究鱼类的这一过程可能有助于我们了解这种病理状态。鱼类使用的第二个新过程涉及它们饮用的海水中高水平的镁和硫酸盐。这些物质不会被吸收，因此随着水被提取，吞咽的液体沿着肠道向下移动，预计会越来越浓缩。这最终会阻碍水渗透到血液中。然而，镁和硫酸盐是不寻常的，只有一半的潜力，其他化合物造成渗透。只是因为海水中硫酸镁含量很高，鱼类才能如此有效地提取水分。这将使用从动物身上取出的肠道组织样本进行探索，并在试管中（体外）研究其水传输特性。许多人类泻药使用硫酸镁（埃普森），因此这项研究可以揭示这些治疗方法实际上是如何工作的。

Vertebrates, including humans, are made up of about 70% water. Balancing water intake and output is obviously vital for health, but most people don't realise the vast internal movements of water going on all the time within their bodies. For example, the kidney, gut and pancreas collectively transport 8 times our total body water volume in and out of these tissues each day. Understanding the mechanisms these organs use, and how the cells that line them (called epithelia) operates this water transport is therefore important. Despite this importance, the mechanism of water transport is still the subject of much debate. Having said that, for more than 50 years it has been understood that the net transport of water requires salts (especially sodium chloride, or NaCl) to be transported in one particular direction first, to then drive fluid transport (secondarily) in the same direction by a process known as osmosis. Despite this consensus the precise route that water transport takes across epithelia is hotly disputed. For example, does it pass through the cell membranes, via special protein called aquaporins? or does it squeeze between the cells? The novelty of the present proposal lies in the discovery of two new mechanisms for influencing water transport that are conceptually very different to the other current areas of debate. These ideas challenge the established dogma by not relying on salt being transported in the same direction as water, representing a fundamental change in our understanding and providing a novel model for the mechanism of water transport in animal epithelia. The discovery has been made by studying how marine fish drink seawater and process this fluid through the intestine to avoid dehydration. Like humans drinking ordinary fluids, these animals first transport NaCl from the gut into the blood, and water then follows by osmosis. However, marine fish have another trick up their sleeve that maximises their water extraction capability. They secrete a different compound called bicarbonate (same as found in baking soda) into the intestine, in the opposite direction to water absorption. This causes a chemical reaction within the swallowed seawater that causes the high levels of calcium it contains to precipitate as solid, white clumps of calcium carbonate (like limestone). These 'gut rocks' are eventually excreted but the advantage to the fish is to reduce the total dissolved compounds in the gut fluid, which in turn makes it easier to extract water into the blood. We propose to study this novel process further by using 3 different species of marine fish (flounder, tilapia and trout) that produce very different quantities of bicarbonate, and are therefore predicted to have different efficiencies of water absorption. Cold and high pressure also inhibit precipitation, so we will compare water absorption in fish at cold temperature and high pressure (in a barometric chamber). Precipitation of carbonate occurs in human diseases such as kidney and pancreatic stones, so studying this process in fish may help us understand this pathological condition. A second novel process that fish use involves the high levels of magnesium and sulphate in the sea water that they drink. These are not absorbed, and would therefore be expected to get more and more concentrated as swallowed fluid moves down the intestine as water is extracted. This would eventually retard the osmosis of water into the blood. However, magnesium and sulphate are unusual in only having half the potential of other compounds to causes osmosis. It is only because seawater happens to have such high levels of magnesium sulphate that fish extract water so efficiently. This will be explored using samples of gut tissue taken out of the animal and studying its water transport properties in a test tube (in vitro). Many human laxatives use magnesium sulphate (Epsom salts) so this research could reveal insights into how these treatments actually work.