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

醛固酮诱导的内皮糖萼功能障碍是蛋白尿的潜在治疗靶点？

• 批准号: MR/M018237/1
• 负责人: Matthew Butler
• 金额: $ 31.93万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM018237%2F1
• 关键词: Aldosterone; induced; endothelial; glycocalyx; dysfunction

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.

健康时，肾脏就像一个过滤器，将细胞和蛋白质保持在血液中，同时允许毒素进入尿液。尿中出现大量蛋白质（蛋白尿）表明肾脏滤过单位，即肾小球已经受损。蛋白尿很常见，影响4%的健康成年人和20%以上的慢性肾脏疾病患者。这是很重要的，因为蛋白尿的存在使个体有更高的进行性肾衰竭、心脏病发作和中风的风险。为了使蛋白质离开血液进入尿液，它必须通过许多细胞层，这些细胞层统称为肾小球滤过屏障。这是肾脏的重要组成部分，通常可以防止蛋白质进入尿液。该屏障由两种类型的细胞组成，足细胞和内皮细胞。内皮细胞是血管中最内层的细胞。内皮细胞被另一层称为糖萼的保护层所覆盖。这一层由内皮细胞产生，是蛋白质和糖的混合物。它在细胞表面形成果冻状的覆盖物。人们发现这一层有许多重要的作用。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，帮助调节组织血流量，防止血液不必要地凝结。到目前为止，已经有许多情况显示会影响糖萼，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渗漏到尿液中。醛固酮是一种帮助动物调节体内盐分和水分的激素。它的主要作用是作用于肾细胞，使其保持体内的钠，并将钾释放到尿液中。当我们健康的时候，我们血液中的醛固酮水平受到严格的调节然而在一些情况下，醛固酮水平会升高，包括；高血压、肥胖、肾衰竭、睡眠障碍和一些药物（包括在英国常用的治疗高血压的ACE抑制剂和血管紧张素受体阻滞剂）。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中泄漏到尿液中的蛋白质数量，从而保持肾功能。阻滞性醛固酮也有助于心脏功能不佳的患者。然而，肾脏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，血液中的钾含量会变得很高。阻断醛固酮会加重这个问题。如果钾含量过高，就会使心脏进入危险的心律。这意味着大多数肾病患者错过了一种可以帮助保持肾脏功能的重要药物。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损害活体动物的糖萼。我认为醛固酮很可能导致细胞产生一种叫做肝素酶的酶。当它被释放到血液中时，这种酶会从糖萼中去除硫酸肝素，破坏其结构。我相信如果我能阻止这个过程，我就能保护糖萼，并有可能减少蛋白尿，而不会引起高钾水平。我将在布里斯托尔大学实验室的一个小组中工作，重点研究肾脏内的糖萼。该小组在涉及糖萼的工作方面享有良好的国际声誉，由肾脏医生领导。作为一名临床医生，我知道临床需要进一步的治疗来减少蛋白尿。研究这一新的途径可能会产生新的治疗靶点，适合临床实践，没有高钾的副作用。

项目成果

Aldosterone: Essential for Life but Damaging to the Vascular Endothelium.

• DOI: 10.3390/biom13061004
• 发表时间: 2023-06-17
• 期刊: Biomolecules
• 影响因子: 5.5

Aldosterone induces albuminuria via matrix metalloproteinase-dependent damage of the endothelial glycocalyx.

醛固酮通过基质金属蛋白酶依赖性糖蛋白糖脂诱导蛋白尿。

• DOI: 10.1016/j.kint.2018.08.024
• 发表时间: 2019-01
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Butler MJ;Ramnath R;Kadoya H;Desposito D;Riquier-Brison A;Ferguson JK;Onions KL;Ogier AS;ElHegni H;Coward RJ;Welsh GI;Foster RR;Peti-Peterdi J;Satchell SC
• 通讯作者: Satchell SC

Heparanase inhibition as a systemic approach to protect the endothelial glycocalyx and prevent microvascular complications in diabetes.

• DOI: 10.1186/s12933-024-02133-1
• 发表时间: 2024-02-01
• 期刊: Cardiovascular diabetology
• 影响因子: 9.3

Shiga toxin targets the podocyte causing hemolytic uremic syndrome through endothelial complement activation.

志贺毒素靶向足细胞，通过激活内皮补体引起溶血性尿毒症综合征。

• DOI: 10.1016/j.medj.2023.09.002
• 发表时间: 2023
• 期刊: Med (New York, N.Y.)
• 作者: Bowen EE

A novel assay provides sensitive measurement of physiologically relevant changes in albumin permeability in isolated human and rodent glomeruli.

• DOI: 10.1016/j.kint.2017.12.003
• 发表时间: 2018-05
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Desideri S;Onions KL;Qiu Y;Ramnath RD;Butler MJ;Neal CR;King MLR;Salmon AE;Saleem MA;Welsh GI;Michel CC;Satchell SC;Salmon AHJ;Foster RR
• 通讯作者: Foster RR