Aldosterone-induced endothelial glycocalyx dysfunction, a potential therapeutic target in proteinuria?

在健康的肾脏作为一个过滤器，保持细胞和蛋白质在我们的血液中，同时允许毒素进入尿液。尿中大量蛋白质的存在（蛋白尿）表明肾脏的过滤单位，称为肾小球，已经受损。蛋白尿是常见的，影响4%的健康成人和超过20%的慢性肾脏疾病患者。蛋白尿的存在使个体发生进行性肾衰竭、心脏病发作和中风的风险更高。蛋白质要离开血液进入尿液，必须穿过统称为肾小球滤过屏障的许多细胞层。这是我们肾脏的重要组成部分，通常会阻止蛋白质进入尿液。该屏障由两种类型的细胞组成，足细胞和内皮细胞。内皮细胞形成我们血管内最内层的细胞。内皮细胞被称为糖萼的额外保护层覆盖。这一层是由内皮细胞产生的，是蛋白质和糖的混合物。它在细胞表面形成胶状物。这一层已经被发现有许多重要的工作。它调节细胞和蛋白质从血液进入组织的通道。它检测血液流动的速度，帮助调节组织的血液流动，并防止血液不必要地凝结。到目前为止，已经有一些条件被证明会影响糖萼，我相信一种叫做醛固酮的激素可能会损害糖萼，这种损害会导致蛋白质泄漏到尿液中。醛固酮是一种激素，可以帮助动物调节体内盐和水的含量。它的主要作用是对肾细胞，使他们保持钠在体内和松散的钾进入尿液。当我们健康时，血液中的醛固酮水平受到严格控制，但在一些情况下，醛固酮水平会增加，包括：高血压，肥胖，肾功能衰竭，睡眠障碍和一些药物（包括ACE抑制剂和血管紧张素受体阻滞剂，在英国常用于治疗高血压）。对蛋白尿患者的临床研究表明，阻断醛固酮可以减少从血液泄漏到尿液中的蛋白质量，从而保护肾功能。阻断醛固酮也有助于心脏功能不佳的患者。然而，肾病医生不愿意开醛固酮阻断药物，因为它们有副作用。在肾脏疾病中，血液中的钾水平可能会升高。阻断醛固酮会使这个问题恶化。如果钾水平过高，可能会使心脏进入危险的节律。这意味着大多数肾病患者错过了一种重要的药物，可以帮助保护他们的肾功能。我在实验室对人类细胞的临时研究表明，醛固酮会破坏糖萼。我研究的下一步是证实醛固酮会损害活体动物的糖萼。我认为很可能是醛固酮导致细胞产生一种叫做乙酰肝素酶的酶。当它被释放到血液中时，这种酶从糖萼中去除硫酸乙酰肝素，破坏其结构。我相信如果我能阻止这一过程，我可以保护糖萼，并可能减少蛋白尿，而不会导致高钾水平。我将在布里斯托大学实验室的一个小组中工作，重点是肾脏内的糖萼。该小组在涉及糖萼的工作方面享有良好的国际声誉，并由肾脏医生领导。作为一名临床医生，我知道临床上需要进一步的治疗来减少蛋白尿。研究这一新途径可能会产生新的治疗靶点，适合于临床实践，没有高钾的副作用。

In health the kidney act as a filter, keeping cells and proteins within our blood whilst allowing toxins to pass into the urine. The presence of a significant quantity of protein in the urine (proteinuria) indicates that the kidney filtering units, called glomeruli, have been damaged. Proteinuria is common affecting 4% of healthy adults and over 20 % of those with chronic kidney disease. It is important because the presence of proteinuria places individuals at a much higher risk of progressive kidney failure, heart attacks and strokes.In order for protein to leave the blood and enter the urine it has to pass through a number of cell layers collectively called the glomerular filtration barrier. This forms a key part of our kidneys and normally prevents protein from entering the urine. The barrier consists of two types of cell, podocytes and endothelial cells. The endothelial cells form the innermost layer of cells within our blood vessels. Endothelial cells are covered by an additional protective layer called the glycocalyx. This layer is produced by the endothelial cells and is a mix of proteins and sugars. It forms a jelly like covering on the cells surface. This layer has been found to have a number of important jobs. It regulates the passage of cells and proteins from the blood into the tissues. It detects how fast the blood is moving helping to regulate tissues blood flow and it prevents blood from clotting unnecessarilySo far a number of conditions have been shown to affect the glycocalyx, I believe that a hormone called Aldosterone is likely to damage the glycocalyx and that this damage results in protein leaking into the urine. Aldosterone is a hormone that helps animals regulate the amount of salt and water in their bodies. Its main action is on kidney cells to make them keep sodium within the body and loose potassium into the urine. When we are healthy the level of aldosterone in our blood is tightly regulated however the levels are increased in a number of conditions including; high blood pressure, obesity, renal failure, sleep disorders and by some medications (including ACE inhibitors and angiotensin receptor blockers which are commonly used in the UK to treat high blood pressure). Clinical studies in patients with proteinuria have shown that blocking aldosterone reduces the amount of protein that leaks from the blood into the urine preserving kidney function. Blocking aldosterone also helps patients with poor heart function. Kidney doctors are reluctant to prescribe aldosterone-blocking drugs, however, because of their side effects. In kidney disease potassium levels in the blood can become high. Blocking aldosterone can worsen this problem. If the potassium level becomes too high it can send the heart into a dangerous rhythm. This means most kidney patients miss out on an important drug that could help preserve their kidney function. My provisional work on human cells in the lab has shown that aldosterone damages the glycocalyx. The next step in my research is to confirm that aldosterone damages the glycocalyx in living animals. I think it is likely that aldosterone causes cells to make an enzyme called heparanase. When this is released into the blood this enzyme removes heparan sulphate from the glycocalyx damaging its structure. I believe if I can prevent this process I can protect the glycocalyx and potentially reduce proteinuria without causing high potassium levels.I will be working in the University of Bristol laboratories within a group focused on the glycocalyx within the kidney. The group has an excellent international reputation for work involving the glycocalyx and is led by renal physicians. In my role as a clinician I know that there is a clinical need for further therapies to reduce proteinuria. Studying this novel pathway may yield new therapeutic targets suitable for clinical practice free from the side effect of high potassium.