Gene Nutrient Interactions in Kidney Function

慢性肾脏疾病（CKD）非常常见，常常导致终末期肾脏疾病（ESRD），因此需要肾脏替代治疗。微量蛋白尿、蛋白尿、超滤过和肾功能受损均与肥胖有关，这表明过量的肾脂质，特别是游离脂肪酸（FFAs），可能通过增加氧化应激和炎症直接损伤和/或间接损害肾脏。肾脂质过多会损害肾小管细胞。免疫炎症途径可诱导氧化应激，导致足细胞损伤和肾元细胞外基质蛋白沉积。使用两种与肥胖相关的肾脏疾病小鼠模型，我们发现维甲酸受体β2 （RARβ2）激动剂保护肾脏免受脂肪毒性。RARβ2是由类维生素a（维生素a的衍生物和代谢物）激活的核转录因子家族的一员。我们假设肾脂质积累是肾小球和肾小管室功能障碍的一个关键因素，这种过量的肾脂质积累可以通过使用RARβ2的高选择性激动剂来预防或逆转。这一假设的一个推论是，这种RARβ2激动剂可以逆转肾功能障碍。我们将在三个方面验证这一假设：在Specific Aim(1)中，我们将测试（在临床前药物疗效研究中）选择性RARβ2激动剂（AC261066, AC55649），以确定这些合成类维生素a是否可以(a)减少肾脏中的脂质沉积，(b)改善或稳定肥胖引起的慢性肾脏疾病的肾功能，表明这些药物可能用于治疗与肥胖相关的CKD患者。我们将使用两种小鼠模型，高脂肪饮食（HFD）诱导的肥胖模型和db/db小鼠，肥胖相关CKD的遗传模型。在Specific Aim(2)中，我们将探讨RARβ2激动剂在这些小鼠模型中减少脂质积累和肾脏炎症的分子机制。Aim(2)还将通过肾细胞类型特异性RARβ敲除小鼠，测试RARβ2激动剂是否通过肾中特定类型细胞中表达的RARβ2起作用。在Specific Aim(3)中，我们将使用细胞培养模型来确定RARβ2激动剂是否通过RARβ2受体作用于足细胞、系膜细胞和/或近端小管细胞。选择性RARβ2激动剂尚未用于治疗肥胖诱导的CKD。因此，我们提出的研究可能会定义一个特定的、新的药物靶点，并确定治疗甚至预防肥胖相关肾病或其他类型CKD的新药。我们应用的优势包括我们发表的研究表明，RARβ2激动剂抑制遗传和饮食性肥胖诱导的小鼠疾病模型中肾脏和肝脏脂肪变性的发展；我们拥有的独特试剂，如条件敲除RARβ小鼠；以及我们在威尔康奈尔大学的研究团队，包括在类维生素a药理学、小鼠模型、肾脏组织学和病理学方面具有丰富经验的研究人员。

Chronic kidney disease (CKD) is quite common and often leads to end-stage renal disease (ESRD) with the resultant need for renal replacement therapy. Micro-albuminuria, proteinuria, hyper-filtration, and impaired renal function occur with obesity, suggesting that excess renal lipids, particularly free fatty acids (FFAs), may directly injure and/or indirectly damage the kidneys via increased oxidative stress and inflammation. An excess of renal lipids can damage renal tubule cells. Immune inflammatory pathways can induce oxidative stress, resulting in podocyte injury and protein deposition in the extracellular matrix of the nephron. Using two different murine models of renal disease associated with obesity, we have discovered that retinoic acid receptor β2 (RARβ2) agonists protect kidneys against lipotoxicity. RARβ2 is a member of a family of nuclear transcription factors that are activated by retinoids (derivatives and metabolites of vitamin A (retinol). We hypothesize that renal lipid accumulation is a key contributor to dysfunction in both the glomerular and tubular compartments and that this excess renal lipid accumulation can be prevented or reversed through the use of highly selective agonists of RARβ2. A corollary to this hypothesis is that renal dysfunction may be reversed by this RARβ2 agonist. We will test this hypothesis in three aims: in Specific Aim (1), we will test (in pre-clinical drug efficacy studies) selective RARβ2 agonists (AC261066, AC55649) to determine if these synthetic retinoids can (a) decrease the lipid deposition in the kidneys and (b) improve or stabilize kidney function in obesity-induced chronic kidney disease, indicating that these drugs could potentially be used to treat human patients who present with CKD associated with obesity. We will use two murine models, a high fat diet (HFD)-induced obesity model and db/db mice, a genetic model of obesity-associated CKD. In Specific Aim (2), we will explore the molecular mechanism(s) by which RARβ2 agonists reduce lipid accumulation and renal inflammation in these mouse models. Aim (2) will also test whether the RARβ2 agonists are acting via RARβ2 expressed in particular types of cells in the kidney through the use of renal cell type specific RARβ knockout mice. In Specific Aim (3), we will use cell culture models to ascertain if RARβ2 agonists act on podocytes, mesangial cells, and/ or proximal tubule cells via the RARβ2 receptor. Selective RARβ2 agonists have not been tested for treatment of obesity-induced CKD. Thus, our proposed research may define a specific, novel drug target and identify new drugs that treat, and even prevent obesity- associated nephropathy or, possibly, other types of CKD. The strengths of our application include our published work showing that the RARβ2 agonists inhibit the development of renal and hepatic steatosis in genetic and dietary obesity-induced murine disease models; the unique reagents in our possession, such as the conditional knockout RARβ mice; and our research team at Weill Cornell that includes researchers with considerable experience in retinoid pharmacology, mouse models, and renal histology and pathology.