Role of FXR and TGR5 in Age Related Renal Diseases

 描述（由申请人提供）：健康老年人的肾功能逐渐下降。衰老可能会加剧急性肾损伤（阿基）和慢性肾脏病（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衰老的重要性及其对老年人阿基，CKD和ESRD的潜在贡献。由于美国65岁以上的人口预计在未来20年内将翻一番，因此关注年龄相关性肾损伤和疾病的潜在早期干预策略变得至关重要。我们将检验以下假设：核激素受体FXR和G蛋白偶联膜受体TGR 5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病中起重要作用，这导致a）线粒体活性氧（ROS）的产生增加和线粒体抗氧化剂的产生减少，引起氧化应激和炎症增加，和B）减少线粒体脂肪酸β-氧化，引起肾脂质积累增加。我们认为FXR和/或TGR 5激动剂或过表达将预防或显着减少与年龄相关的肾小球滤过率（GFR）下降、白蛋白尿增加、足细胞丢失和细胞外基质蛋白积聚a）减少线粒体活性氧（ROS）的产生和增加线粒体抗氧化剂的产生，导致氧化应激和炎症减少，和B）线粒体脂肪酸β-氧化增加，导致肾脂质积累减少。在特定目的1中，我们将确定FXR和TGR 5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，以确定肾脏胆汁酸组成的改变如何调节足细胞功能。在SPECIFIC AIM 2中，我们将进行机制研究，以确定FXR和TGR 5是否通过Sirtuin 3依赖性机制预防年龄相关性肾病。影响与创新：1）迄今未认识到的以下作用：i）核受体FXR，ii）G蛋白偶联受体TGR 5和iii）双重FXR/TGR 5激动剂作为治疗剂用于治疗年龄相关性肾病和并发症的潜力。2)FXR和TGR 5激动剂在调节线粒体功能、氧化应激、炎症和脂质代谢中的新颖且独特的作用，因为它们与年龄相关的肾病相关。3)TGR 5/FXR信号传导模拟热量限制（CR），可能导致年龄相关性肾损伤和并发症的新干预策略。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.