Fructokinase and Nondiabetic and Aging-Associated Chronic Kidney Disease

果糖激酶与非糖尿病和衰老相关的慢性肾脏病

• 批准号: 8966551
• 负责人: Richard Joseph Johnson
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8966551
• 关键词: Accounting; Acute; Adenine; Affect; Age; Age-Months; Age-Years; Aging; Aldehyde Reductase; Automobile Driving; Blood Glucose; Carbohydrates; Chronic Kidney Failure; Complex; Data; Dehydration; Diabetes Mellitus; Diabetic Nephropathy; Diet; Dietary Intervention; Disease; Disease Progression; Doxycycline; Enzymes; Epidemic; Fatty acid glycerol esters; Fructokinases; Fructose; Glucose; Goals; Health; Hypertension; Individual; Inflammatory Response; Injury; Intake; Ketohexokinase; Kidney; Kidney Diseases; Knock-out; Knockout Mice; Lead; Life; Link; Measures; Mediating; Metabolic syndrome; Metabolism; Modeling; Mus; Obesity; Oral; Oxidative Stress; Pathway interactions; Phenotype; Population; Prevalence; Process; Proteins; Proximal Kidney Tubules; Randomized; Rattus; Recurrence; Renal tubule structure; Renin-Angiotensin System; Risk Factors; Role; Sucrose; Testing; Therapeutic Intervention; Tubular formation; United States; Veterans; Weaning; Wild Type Mouse; Work; base; blood pressure regulation; chemokine; diabetic; feeding; insight; non-diabetic; novel; polyol; prevent; sugar; western diet

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) is increasing in prevalence and affects more than 20 million individuals in the United States, and is especially common among veterans. Some causes are well known, such as diabetes and hypertension, and current management remains similar to two decades ago and consists of blood pressure control, blood sugar control, and blockade of the renin angiotensin system. More recently, we find that CKD is developing in people before they develop diabetes and hypertension, such as in subjects with metabolic syndrome, and also is developing in almost everyone as we age. Furthermore, once we have CKD, progression of kidney disease tends to continue despite our best efforts. It seems like there must be some other risk factor that has not been identified. In this proposal we present a novel hypothesis that our western diet may be driving subtle kidney disease in everyone. Specifically, we suggest that a little-known enzyme in the kidney proximal tubule, known as fructokinase, may be driving much of the current CKD epidemic. Fructokinase is an enzyme that metabolizes fructose and in the process causes intracellular ATP depletion, oxidative stress, and an inflammatory response. Diets high in sugars containing fructose can cause acute and chronic kidney disease in rats, likely due to metabolism of fructose in the proximal tubule. Recently we found that fructose can also be generated from glucose in the proximal tubule when the enzyme aldose reductase is induced, and preliminary studies suggest this may have a role in diabetic and nondiabetic CKD and also in aging-associated CKD. We therefore hypothesize that low grade fructose metabolism by fructokinase in the proximal tubule is the missing link that explains why CKD is increasing, why CKD is associated with metabolic syndrome, why CKD is occurring with aging, and why kidney disease progresses in subjects with preexisting CKD. To test these hypotheses, we will do the following studies. Aim 1 will evaluate the role of fructokinase in the CKD associated with aging and metabolic syndrome, and will also determine if CKD is accelerated by simple sugars containing fructose, sucrose, or glucose compared to complex carbohydrates. Models will include normal mice and mice with metabolic syndrome (Pound mouse) that either express fructokinase or have fructokinase systemically absent. Aim 2 will determine if fructokinase has a role in the renal progression that occurs in established CKD and whether it is accelerated by simple sugars via this mechanism. Aim 3 will test the hypothesis that it is renal fructokinase that is driving aging-associated CKD and the progression of kidney disease in established CKD using mice in which fructokinase is selectively deleted from the kidney. If successful, these studies will identify a novel mechanism driving CKD that could be as important a factor as hypertension and diabetes themselves. Furthermore, our studies should be able to determine if altering the composition of simple sugars in the diet can influence progression. These discoveries could therefore lead to both dietary measures, as well as potentially new treatments to prevent CKD in veterans and others living in western cultures.

描述（由申请人提供）： 慢性肾脏疾病（CKD）的患病率正在增加，在美国影响超过2000万人，在退伍军人中尤为常见。一些原因是众所周知的，例如糖尿病和高血压，并且当前的管理仍然与两十年前相似，包括血压控制，血糖控制和肾素血管紧张素系统的阻塞。最近，我们发现CKD在患者发展糖尿病和高血压之前正在发展，例如患有代谢综合征的受试者，并且随着年龄的增长，几乎每个人都在发展。此外，一旦我们拥有CKD，尽管我们尽了最大的努力，但肾脏疾病的进展仍会继续。似乎一定有其他尚未确定的风险因素。在此提案中，我们提出了一个新的假设 我们的西方饮食可能会吸引每个人的微妙肾脏疾病。具体而言，我们建议在肾脏近端小管中鲜为人知的酶（称为果糖酶）可能正在驱动当前的CKD流行。果糖酶是一种代谢果糖，在此过程中会导致细胞内ATP耗竭，氧化应激和炎症反应。含糖含量高的饮食可能会导致大鼠急性和慢性肾脏疾病，这可能是由于近端小管中果糖的代谢所致。最近，我们发现，当诱导酶醛糖还原酶时，还可以通过近端小管中的葡萄糖产生果糖，并且初步研究表明，这可能在糖尿病和非糖尿病性CKD以及与衰老相关的CKD中起作用。因此，我们假设在近端小管中果糖酶代谢的低级果糖代谢是缺失的联系，它解释了CKD的增加原因，为什么CKD与代谢综合征相关，为什么CKD与衰老发生有关，以及为何在受试者中随着Preexisting CKD的肾脏疾病进展。为了检验这些假设，我们将进行以下研究。 AIM 1将评估果糖酶在与衰老和代谢综合征相关的CKD中的作用，并且还将确定与复杂的碳水化合物相比，含有果糖，蔗糖或葡萄糖的简单糖是否会加速CKD。模型将包括正常的小鼠和具有代谢综合征（磅小鼠）的小鼠，这些小鼠要么是表达果糖酶或具有果糖酶在系统上不存在的小鼠。 AIM 2将确定果糖酶是否在已建立的CKD中发生的肾脏进展中起作用，以及它是否通过这种机制通过简单糖加速。 AIM 3将检验以下假设：肾脏果味酶正在驱动与衰老相关的CKD和使用果糖酶从肾脏中选择性删除的果糖酶的小鼠在已建立的CKD中的肾脏疾病进展。如果成功，这些研究将确定一种驱动CKD的新型机制，这可能是高血压和糖尿病本身一样重要的因素。此外，我们的研究应该能够确定改变饮食中简单糖的组成是否会影响进展。因此，这些发现可能会导致饮食措施，以及潜在的新疗法，以防止退伍军人和其他生活在西方文化中的CKD。