Role of FXR and TGR5 in Age Related Renal Diseases

FXR 和 TGR5 在年龄相关性肾脏疾病中的作用

• 批准号: 9346676
• 负责人: MOSHE LEVI
• 金额: $ 7.28万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2017-10-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9346676
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adult; Affect; Age; Aging; Agonist; Albumins; Albuminuria; Antioxidants; Attenuated; Baltimore; Bile Acids; Biogenesis; Blood Vessels; Caloric Restriction; Chronic Kidney Failure; Cicatrix; Coupled; Development; Disease; Early Intervention; Elderly; End stage renal failure; Excretory function; Extracellular Matrix; Extracellular Matrix Proteins; Fatty Acids; Fibrosis; G-Protein-Coupled Receptors; G-substrate; GPBAR1 gene; GTP-Binding Proteins; Gender; Generations; Glomerular Filtration Rate; Impairment; Individual; Inflammation; Injury; Intervention; Kidney; Kidney Diseases; Knock-out; Knockout Mice; Lipids; Longitudinal Studies; Membrane; Mitochondria; Molecular; Mus; Nuclear Hormone Receptors; Nuclear Receptors; Older Population; Oxidative Stress; Play; Process; Race; Reactive Oxygen Species; Regulation; Renal Tissue; Renal function; Role; SIRT1 gene; Sclerosis; Signal Transduction; Sirtuins; Testing; Therapeutic Agents; Time; Transgenic Mice; United States; Variant; age related; aged; farnesoid X-activated receptor; glomerulosclerosis; healthy aging; improved; innovation; interstitial; lipid metabolism; novel; overexpression; oxidation; podocyte; prevent; public health relevance; receptor; urinary

 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.

 描述（由申请人提供）： 健康老龄化个体的肾功能逐渐衰退，大约一半以上的 CKD 病例和大多数晚期肾病可能会恶化。肾脏疾病（ESRD）发生在老年人群中，这些发现凸显了肾脏衰老的重要性及其对老年人 AKI、CKD 和 ESRD 的潜在影响。预计在未来 20 年美国将增加一倍，关注与年龄相关的肾损伤和疾病的潜在早期干预策略变得至关重要，我们将检验核激素受体 FXR 和 G 蛋白偶联膜与年龄相关的减少的假设。受体 TGR5 表达通过损害线粒体功能在与年龄相关的肾脏疾病中发挥重要作用，这会导致 a) 线粒体活性氧 (ROS) 生成增加，线粒体抗氧化剂生成减少，导致氧化应激和炎症增加，b)减少线粒体脂肪酸β-氧化，导致肾脂质积累增加，我们认为 FXR 和/或 TGR5 激动剂或过度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、足细胞丢失和积累。通过改善线粒体功能来减少细胞外基质蛋白（纤维化），这会导致 a) 线粒体活性氧 (ROS) 的产生减少，线粒体抗氧化剂的产生增加，从而导致氧化应激和炎症，b) 线粒体脂肪酸β-氧化增加，导致肾脏脂质积累减少。在具体目标 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。研究以确定肾脏胆汁酸成分的变化如何调节足细胞功能 在具体目标 2 中，我们将进行机制研究以确定 FXR 和 TGR5 是否可以预防足细胞功能。 Sirtuin 3 依赖性肾脏机制对年龄相关疾病的影响和创新：1) 迄今为止尚未认识到的作用：i) 核受体 FXR，ii) G 蛋白偶联受体 TGR5 和 iii) FXR/TGR5 双重激动剂作为治疗药物的潜力。 2) FXR 和 TGR5 激动剂在调节线粒体功能、氧化应激、炎症和脂质方面的新颖且独特的作用。代谢，因为它们与年龄相关的肾脏疾病相关。 3) TGR5/FXR 信号传导模仿热量限制 (CR)，可能导致针对年龄相关肾损伤和并发症的新干预策略。 4) 确定其作用的机制研究。胆汁酸和线粒体 Sirtuin 3 在调节年龄相关性肾病中的作用。