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）： 慢性肾病 (CKD) 的患病率正在上升，影响着美国超过 2000 万人，其中在退伍军人中尤其常见。有些病因是众所周知的，例如糖尿病和高血压，目前的治疗方法仍然与二十年前相似，包括控制血压、控制血糖和阻断肾素血管紧张素系统。最近，我们发现慢性肾病（CKD）在人们罹患糖尿病和高血压之前就已经发生，例如代谢综合征患者，并且随着年龄的增长，几乎每个人都在发生慢性肾病（CKD）。此外，一旦我们患有 CKD，尽管我们尽了最大努力，肾脏疾病的进展往往会持续下去。看来一定还有其他尚未确定的风险因素。在这个提案中，我们提出了一个新的假设 我们的西方饮食可能会导致每个人患上微妙的肾脏疾病。具体来说，我们认为肾近曲小管中一种鲜为人知的酶（称为果糖激酶）可能是当前 CKD 流行的主要原因。果糖激酶是一种代谢果糖的酶，在此过程中会导致细胞内 ATP 消耗、氧化应激和炎症反应。含果糖含量高的饮食可导致大鼠急性和慢性肾脏疾病，这可能是由于近曲小管中果糖的代谢所致。最近我们发现，当醛糖还原酶被诱导时，近曲小管中的葡萄糖也可以产生果糖，初步研究表明这可能在糖尿病和非糖尿病 CKD 以及衰老相关 CKD 中发挥作用。因此，我们假设近曲小管中果糖激酶的低级果糖代谢是解释为什么 CKD 增加、为什么 CKD 与代谢综合征相关、为什么 CKD 随年龄增长而发生以及为什么肾脏疾病在已有 CKD 的受试者中进展的缺失环节。为了检验这些假设，我们将进行以下研究。目标 1 将评估果糖激酶在与衰老和代谢综合征相关的 CKD 中的作用，还将确定与复杂碳水化合物相比，含有果糖、蔗糖或葡萄糖的单糖是否会加速 CKD。模型将包括正常小鼠和患有代谢综合征的小鼠（磅小鼠），它们表达果糖激酶或全身缺乏果糖激酶。目标 2 将确定果糖激酶是否在已确定的 CKD 中发生的肾脏进展中发挥作用，以及单糖是否通过这种机制加速肾脏进展。目标 3 将使用从肾脏中选择性删除果糖激酶的小鼠来测试肾果糖激酶正在驱动与衰老相关的 CKD 以及已确定的 CKD 中肾脏疾病的进展这一假设。如果成功，这些研究将确定一种驱动 CKD 的新机制，该机制可能与高血压和糖尿病本身一样重要。此外，我们的研究应该能够确定改变饮食中单糖的成分是否会影响进展。因此，这些发现可能会导致退伍军人和生活在西方文化的其他人的饮食措施以及预防慢性肾病的潜在新疗法。