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 在美国很常见的综合症。慢性肾脏病影响着世界上10%以上的人口， 是不断增加的全球健康负担。CKD在美国的患病率约为12-14%。糖尿病和 约三分之二的CKD患者是由高血压引起的，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都与重大 心血管并发症。因此，无论是CKD的新疗法还是对CKD的更深层次的理解 CKD的发生机制亟待研究。维生素A(全反式视黄醇，VA)，一种微量营养素和基本维生素 生活必需品，只能从我们的饮食中获得。肾脏需要维生素A(视黄醇) 但人们对这种重要的微量营养素--维生素A在体内的功能知之甚少 成人肾脏。维生素A的代谢物(如维甲酸)主要通过与三种不同的 视黄酸受体(RARs)和修饰转录。 在R01DK113088中，我们假设R01DK113088是2017年12月资助的新R01拨款，RARβ扮演了一个 RARβ_2选择性激动剂对慢性肾脏病的保护作用及对慢性肾脏病的抑制作用 与肥胖有关。我们已经证明了这些假设，我们将在令人兴奋的结果和 将我们的研究扩展到新的但互补的方向。我们对AIM(1)的假设是RARβ2 选择性激动剂AC261066将有效地减少多种类型肾脏的病理后遗症 损伤，而不仅仅是与脂肪毒性相关的损伤与肥胖引起的慢性肾脏疾病有关。对于AIM(2)，我们 假设维生素A通过每个维甲酸受体，包括我们刚刚开始研究的RARγ， 在成人肾脏中对多种不同类型的细胞起关键作用，在特定肾脏中缺乏RARS的小鼠 细胞可能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激动剂对慢性肾脏病的发展有治疗作用。 在一个小鼠模型中，我们建议测试这种RARβ2激动剂在另外两个慢性肾脏病中的疗效。 模型，潜在地创造了使用AC261066作为先导化合物治疗CKD和 来确定它的基因靶点。特定目标(2)：我们研究微量营养素维生素A的遗传学方法 取得了丰硕成果，并产生了各种类型的慢性肾脏病的几个潜在有用的模型。 此外，我们的结果表明，肾脏与其他器官系统的相互作用在 不同的鼠标型号。因此，我们建议评估维甲酸受体α，β的作用，以及 肾脏中特定细胞类型的γ。通过这项研究，我们将了解KKD的病理机制 更深入地阐明这些病理与营养和维生素A信号异常之间的关系， 发现新的、有用的CKD模型，推进治疗CKD的新疗法的开发。

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.