Gene Nutrient Interactions in Kidney Function

急性肾脏病（AKD）和慢性肾脏病（CKD）是相互关联的，病理性的， 这些症状在美国很常见。CKD影响超过10%的世界人口， 这是一个日益严重的全球健康负担。CKD在美国的患病率约为12- 14%。糖尿病和 高血压引起约三分之二CKD病例，而肾小球肾炎、肾结石、多囊肾 疾病和毒物是不太常见的原因。AKD和CKD都与主要的 心血管并发症因此，新的CKD治疗方法和更深入地了解 CKD的发生是非常需要的。维生素A（全反式视黄醇，VA），微量营养素和必需维生素 生命所必需的，只能从我们的饮食中获得。维生素A（视黄醇）是肾脏所必需的 维生素A是一种重要的微量营养素，但对维生素A的功能知之甚少， 成人肾脏维生素A的代谢产物（如视黄酸（RA））主要通过与三种不同的维生素A结合而起作用。 视黄酸受体（RARs）和修饰转录。 在R 01 DK 113088中，2017年12月资助的一项新的R 01拨款，我们假设RARβ发挥了 对CKD的保护作用，RARβ2选择性激动剂可抑制CKD的发展 与肥胖有关。我们已经证明了这些假设，我们将建立在我们令人兴奋的结果， 将我们的研究扩展到新的，但互补的方向。我们对目标（1）的假设是RARβ2 选择性激动剂AC 261066将有效减少一种以上类型肾移植后的病理后遗症 损伤，而不仅仅是与肥胖引起的慢性肾脏疾病相关的脂毒性相关损伤。对于目标（2），我们 假设维生素A通过每个视黄酸受体，包括我们刚刚开始研究的RARγ， 在成年肾脏的多种不同细胞类型中具有关键作用， 细胞可以是各种人类肾脏疾病的模型。我们提出两个具体目标：具体目标（1）：因为 我们有证据表明选择性RARβ2激动剂对CKD的发展具有治疗作用， 在一个小鼠模型中，我们建议测试这种RARβ2激动剂在另外两种CKD中的疗效 模型，可能为使用AC 261066作为治疗CKD的先导化合物提供依据， 来定义它的基因靶点。具体目标（2）：我们研究微量营养素维生素A的遗传方法 已经取得了丰硕的成果，并产生了几个潜在的有用模型的各种类型的CKD。 此外，我们的研究结果表明，肾脏与其他器官系统的相互作用在不同的 不同的小鼠模型。因此，我们建议评估视黄酸受体α，β和 γ在肾脏的特定细胞类型中。通过这项研究，我们将了解CKD的病理学 更深入地，阐明这些病理学如何与营养和异常维生素A信号传导相关， 发现新的、有用的CKD模型，并推进CKD新疗法的开发。

Acute kidney disease (AKD) and chronic kidney disease (CKD) are interconnected, pathological syndromes that are quite common in the USA. CKD affects greater than 10% of the world’s population and is an increasing global health burden. The prevalence of CKD in the USA is ~12-14%. Diabetes and hypertension cause ~ two-thirds of CKD cases, while glomerulonephritis, nephrolithiasis, polycystic kidney disease, and toxicants are less common causes. Both AKD and CKD are associated with major cardiovascular complications. Thus, both new treatments for CKD and a deeper understanding of the genesis of CKD are greatly needed. Vitamin A (all-trans retinol, VA), a micronutrient and essential vitamin necessary for life, can only be obtained from our diets. Vitamin A (retinol) is required for kidney development, but much less is known about the functions of this important micronutrient, vitamin A, in the adult kidney. Vitamin A’s metabolites (e.g. retinoic acid (RA)) primarily act by binding to three distinct retinoic acid receptors (RARs) and modifying transcription. In R01 DK113088, a new R01 grant funded in December, 2017, we hypothesized that RARβ played a protective role against CKD and that a RARβ2 selective agonist could inhibit the development of CKD associated with obesity. We have proved these hypotheses and we will build on our exciting results and expand our research into new, but complementary directions. Our hypothesis for Aim (1) is that the RARβ2 selective agonist, AC261066, will be effective in reducing the pathological sequelae after more than one type of kidney injury, not just lipotoxicity-related injury associated with obesity-induced chronic kidney disease. For Aim (2), we hypothesize that vitamin A, via each retinoic acid receptor, including RARγ, which we are just beginning to study, has key actions in multiple, different cell types in the adult kidney and that mice deficient in RARs in specific kidney cells may be models of various human kidney diseases. We propose two specific aims: Specific Aim (1): Because we have evidence that a selective RARβ2 agonist has a therapeutic impact on the development of CKD in one mouse model, we propose to test the efficacy of this RARβ2 agonist in two additional CKD models, potentially creating a rationale to use AC261066 as a lead compound for treatment of CKD and to define its gene targets. Specific Aim (2): Our genetic approach to study the micronutrient vitamin A has been fruitful and has generated several potentially useful models of various types of CKD. Furthermore, our results suggest that the interaction of the kidney with other organ systems varies in different mouse models. Thus, we propose to evaluate the actions of the retinoic acid receptors α, β, and γ in specific cell types in the kidney. We will, through this research, understand the pathologies of CKDs in more depth, elucidate how these pathologies relate to nutrition and aberrant vitamin A signaling, discover new, useful models of CKD, and advance the development of a novel therapeutic for CKD.