Role of FXR and TGR5 in Age Related Renal Diseases

 描述(由申请人提供)：肾功能逐渐下降发生在健康的老年个体中。衰老可加重急性肾损伤(AKI)和慢性肾脏疾病(CKD)。大约一半以上的CKD病例和大多数终末期肾病(ESRD)发生在老年人群中。这些发现强调了肾脏老化的重要性及其对老年人AKI、CKD和ESRD的潜在贡献。由于美国65岁以上的人口预计将在未来20年内翻一番，因此关注与年龄相关的肾脏损伤和疾病的潜在早期干预策略变得至关重要。我们将验证这一假设，即核激素受体FXR和G蛋白偶联膜受体TGR5表达的年龄相关性降低通过损害线粒体功能在年龄相关性肾脏疾病中发挥重要作用，其结果如下：a)线粒体活性氧物种(ROS)的生成增加，线粒体抗氧化剂的生成减少，导致氧化应激和炎症增加，以及b)线粒体脂肪酸氧化减少，导致肾脏脂质堆积增加。我们认为，FXR和/或TGR5激动剂或过表达将通过改善线粒体功能来防止或显著减少与年龄相关的肾小球滤过率(GFR)下降、蛋白尿增加、足细胞丢失和细胞外基质蛋白(纤维化)的积累，从而导致a)线粒体活性氧物种(ROS)的生成减少和线粒体抗氧化剂的生成增加，从而减少氧化应激和炎症，以及b)增加线粒体脂肪酸的氧化，导致肾脏脂质堆积减少。在特定的目标1中，我们将确定FXR和TGR5在年龄相关性肾脏疾病进展中的作用。我们还将进行机制研究，以确定肾脏胆汁酸成分的变化如何调节足细胞功能。在特定的AIM 2中，我们将进行机制研究，以确定FXR和TGR5是否通过Sirtuin 3依赖机制对年龄相关性肾脏疾病具有保护作用。影响和创新：1)迄今尚未认识到的作用：i)核受体FXR，ii)G蛋白偶联受体TGR5和iii)双重FXR/TGR5激动剂作为治疗与年龄相关的肾脏疾病和并发症的药物的潜力。2)FXR和TGR5激动剂在调节线粒体功能、氧化应激、炎症和脂质代谢方面的新的和独特的作用，因为它们与年龄相关的肾脏疾病有关。3)TGR5/FXR信号类似于热量限制(CR)，可能导致新的治疗年龄相关性肾损伤和并发症的策略。4)确定胆汁酸和线粒体Sirtuin 3在调节年龄相关性肾病中的作用的机制研究。

 DESCRIPTION (provided by applicant): A gradual decline in renal function occurs in healthy aging individuals. Aging may exacerbate Acute Kidney Injury (AKI) and Chronic Kidney Disease (CKD). About more than half of the CKD cases and majority of the end stage renal disease (ESRD) occur in the older population. These findings highlight the importance of kidney aging and its potential contribution to AKI, CKD and ESRD in the elderly. Since the population older than 65 years in the United States is expected to double during the next 20 years, focus on potential early intervention strategies for age-associated renal injury and disease becomes critical. We will test the hypothesis that the age-related decreases in nuclear hormone receptor FXR and G protein coupled membrane receptor TGR5 expression play an important role in age-related kidney disease by impairing mitochondrial function, which results in a) increased generation of mitochondrial reactive oxygen species (ROS) and decreased generation of mitochondrial antioxidants, causing increased oxidative stress and inflammation, and b) decreased mitochondrial fatty acid ß-oxidation, causing increased renal lipid accumulation. We propose that FXR and/or TGR5 agonists or overexpression will prevent or markedly reduce age-related decline in glomerular filtration rate (GFR), increase in albuminuria, podocyte loss, and accumulation of extracellular matrix proteins (fibrosis) by improving mitochondrial function, which results in a) decreased generation of mitochondrial reactive oxygen species (ROS) and increased generation of mitochondrial antioxidants, causing decreased oxidative stress and inflammation, and b) increased mitochondrial fatty acid ß-oxidation, causing decreased renal lipid accumulation. In SPECIFIC AIM 1, we will determine the role of FXR and TGR5 in progression of age-related renal disease. We will also perform mechanistic studies to determine how alterations in kidney bile acid composition regulate podocyte function. In SPECIFIC AIM 2, we will perform mechanistic studies to determine if FXR and TGR5 protect against age-related renal disease by Sirtuin 3 dependent mechanisms. Impact and Innovation: 1) The hitherto unrecognized roles of: i) nuclear receptor FXR, ii) G protein coupled receptor TGR5 and iii) the potential of dual FXR/TGR5 agonists as therapeutic agents for treating age- associated renal disease and complications. 2) The novel and distinct role of FXR and TGR5 agonists in regulation of mitochondrial function, oxidative stress, inflammation, and lipid metabolism, as they relate to age- associated renal conditions. 3) TGR5/FXR signaling mimics that of caloric restriction (CR), potentially leading to new intervention strategies for age-related kidney injury and complications. 4) Mechanistic studies to determine the roles of the bile acids and mitochondrial Sirtuin 3 in modulation of age-related renal disease.