Role of gut bacteria and renal lipids in obesity-related kidney disease

项目概要/摘要 肥胖影响美国三分之一的成年人。在与肥胖相关的健康问题中， 慢性肾脏疾病（CKD）和CKD进展的风险更高。协会 肥胖和慢性肾病之间的关系仍然存在，即使在对糖尿病和高血压进行统计调整后， 已知的CKD风险因素通常存在于肥胖人群中。这表明肥胖本身， 独立于其他合并症，有助于CKD。肥胖症的致病机制 对CKD的认识不完全。这个项目测试了一个高度创新的模型， 在人类病理生理学和微生物生物学的多个领域有新的发现。该模型分为 三个概念上相互关联但可独立检验的假设：1.肥胖相关 通常存在于肠道中的微生物的改变导致微生物产生过量的酸， 新陈代谢.这种多余的酸被肠道吸收，然后由肾脏排出，因为肾脏 其任务是防止过量的酸在体内积聚。2.肾脏排酸过多 要求增加谷氨酰胺代谢产生铵（重要的酸排泄），但由于 产生的谷氨酰胺代谢物在细胞中用于产生能量，这减少了其他代谢物的利用。 能量底物，如脂肪酸通过底物竞争。反过来，这使得更多的脂肪酸可用 进入替代代谢途径，导致肾脏脂质蓄积（脂肪变性）和毒性作用 （脂毒性）。3.最后，过量的酸排泄通过减少脂肪酸而促进CKD进展。 利用，脂肪变性和脂毒性，这种影响是更糟的事实，肾脏脂质代谢是 已经被肥胖困扰。这些假设将使用体外、动物和 人体研究采用了磁共振成像、核磁共振成像和核磁共振成像等最新技术， 共振光谱，无菌小鼠研究和靶向小鼠遗传学，结合经典的 生理学和生物化学。总之，本项目旨在通过先前的测试来推进该领域 未探索的，但明确和合理的假设，将肥胖，肠道微生物， 肾脏、肾脏脂质异常和CKD进展。该项目将产生新的知识， 形成新的逻辑干预措施的基础，以防止CKD进展。这是为了配合总体 NIH的使命是通过科学改善人类健康。

PROJECT SUMMARY / ABSTRACT Obesity affects 1 in 3 adults in the United States. Among the health problems associated with obesity is a higher risk for the development of chronic kidney disease (CKD) and for CKD progression. The association between obesity and CKD persists even after statistical adjustment for diabetes and hypertension, which are known CKD risk factors that are often present in people with obesity. This suggests that obesity itself, independent of other comorbid conditions, contributes to CKD. The pathogenic mechanisms linking obesity to CKD are incompletely understood. This project tests a highly innovative model integrating existing knowledge with new findings in multiple areas of human pathophysiology and microbial biology. This model is divided into three hypotheses that are conceptually interrelated but independently testable: 1. Obesity-associated alterations in the microbes that normally reside in the intestine lead to excess acid production by microbial metabolism. This excess acid is absorbed by the intestine and then excreted by the kidney, as the kidney is tasked with preventing excess acid from accumulating in the body. 2. Excess acid excretion by the kidney mandates increased glutamine metabolism to generate ammonium (important for acid excretion), but since the resulting glutamine metabolites are used in the cell to generate energy, this reduces the utilization of other energy substrates such as fatty acids by substrate competition. In turn, this makes more fatty acids available for entry into alternative metabolic pathways, resulting in renal lipid accumulation (steatosis) and toxic effects (lipotoxicity). 3. Finally, excess acid excretion contributes to CKD progression via decreased fatty acid utilization, steatosis and lipotoxicity, and this effect is made worse by the fact that kidney lipid metabolism is already disturbed in obesity. These hypotheses will be tested using a combination of in vitro, animal and human studies employing some of the latest technologies in magnetic resonance imaging, nuclear magnetic resonance spectroscopy, germ-free mouse research and targeted mouse genetics, combined with classical physiology and biochemistry. In summary, this project aims to advance the field by testing previously unexplored, but clear and plausible hypotheses linking obesity, intestinal microbes, increased acid excretion by the kidney, kidney lipid abnormalities, and CKD progression. This project will generate new knowledge that will form the basis for new logical interventions to prevent CKD progression. This is in keeping with the overarching mission of the NIH of improving human health through science.