Fructokinase and Nondiabetic and Aging-Associated Chronic Kidney Disease

描述(由申请人提供)： 慢性肾脏疾病(CKD)的患病率正在上升，在美国有2000多万人受到影响，尤其是在退伍军人中。一些病因是众所周知的，如糖尿病和高血压，目前的治疗仍与20年前类似，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CKD在人们发展为糖尿病和高血压之前就已经发展起来了，比如代谢综合征的受试者，而且随着年龄的增长，几乎每个人都会发展起来。此外，一旦我们有CKD，肾脏疾病的进展往往会继续，尽管我们尽了最大的努力。似乎一定还有其他一些风险因素尚未确定。在这个提议中，我们提出了一个新的假设 我们的西式饮食可能会导致每个人都患上微小的肾脏疾病。具体地说，我们认为，肾脏近端小管中一种鲜为人知的酶，即果糖激酶，可能是目前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耗竭、氧化应激和炎症反应。富含果糖的饮食可能会导致大鼠的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，当醛糖还原酶被诱导时，近端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以及与衰老相关的CKD中起作用。因此，我们假设近端小管果糖激酶的低度果糖代谢是CKD增加、CKD与代谢综合征相关、CKD随着年龄增长而发生以及既往存在CKD的受试者肾脏疾病进展的缺失环节。为了检验这些假设，我们将进行以下研究。目的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，并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代谢综合征小鼠(磅小鼠)，这些小鼠要么表达果糖激酶，要么系统缺乏果糖激酶。目标2将确定果糖激酶是否在已建立的CKD的肾脏进展中起作用，以及单糖是否通过这一机制加速肾脏进展。目的3将利用果糖激酶选择性地从肾脏中删除的小鼠，验证肾脏果糖激酶是导致衰老相关CKD和肾脏疾病进展的假说。如果成功，这些研究将确定一种新的驱动CKD的机制，它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组成是否会影响病情进展。因此，这些发现可能会导致饮食措施，以及潜在的预防退伍军人和其他生活在西方文化中的CKD的新疗法。

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.