Mitochondrial Bioenergetics in the Kidney: Sex-specific Computational Modelling

肾脏中的线粒体生物能学：性别特异性计算模型

• 批准号: 577083-2022
• 负责人: Layton, AnitaAT
• 金额: $ 1.82万
• 依托单位: University of Waterloo
• 依托单位国家: 加拿大
• 项目类别: Alliance Grants
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=743654
• 关键词: Mitochondrial; Bioenergetics; Kidney; Sex; specific

The renal tubules reabsorb >99% of the glomerular filtrate, in part via active transport processes that necessitate energy utilization. The transcellular concentration gradients that drive tubular transport are primarily established by Na+-K+-ATPase pumps that use ATP hydrolysis as a source of energy, which, in turn, requires a sustained rate of ATP generation, mostly by aerobic processes. The kidneys thus have the second highest O2 consumption rate after the heart. The greatest density of mitochondria is found in the proximal tubules and thick ascending limbs. Despite the great importance of renal metabolism and wide recognition of the role of cellular metabolism in other diseases, relatively few studies have focused on these aspects in the development of hypertension. Recent studies in humans and animal models, however, have stirred mounting interest in the role that alterations of renal substrate and energy metabolism may play in hypertension, although the molecular basis and relevance of these metabolic derangements remain largely unknown, and most studies have been primarily descriptive. To fill these knowledge gaps, international collaborators Cowley Jr and Dash are conducting experiments that will provide the needed data for a quantitative understanding of the cellular and molecular mechanisms underlying the development of oxidative stress and reduced efficiency of mitochondrial O2 utilization for ATP production in the kidney during the development of salt-sensitive hypertension. As the Canadian collaborator, Layton and her group will develop computational models that will provide a unique quantitative and mechanistic framework enabling testable predictions of the complex relationships existing between mitochondrial O2 utilization, energy production, and oxidative stress in the kidney during the development of salt-sensitive hypertension. Separate models will be developed for males and females, to study sex differences in these processes. Identification of new and sex-specific therapeutic targets could thereby emerge.

肾小管重吸收>99%的肾小球滤液，部分通过需要能量利用的主动运输过程。驱动肾小管转运的跨细胞浓度梯度主要由Na+-K+-ATP酶泵建立，该泵使用ATP水解作为能量来源，而ATP水解又需要持续的ATP生成速率，主要是通过有氧过程。因此，肾脏具有仅次于心脏的第二高O2消耗率。线粒体密度最大的是近端小管和粗的上升支。尽管肾脏代谢的重要性和细胞代谢在其他疾病中的作用得到广泛认可，但相对较少的研究集中在高血压发展的这些方面。然而，最近在人类和动物模型中的研究已经引起了人们对肾脏底物和能量代谢改变在高血压中可能发挥的作用的越来越大的兴趣，尽管这些代谢紊乱的分子基础和相关性在很大程度上仍然未知，并且大多数研究主要是描述性的。为了填补这些知识空白，国际合作者Cowley Jr和Dash正在进行实验，这些实验将提供所需的数据，用于定量了解氧化应激发展的细胞和分子机制，以及盐敏感性高血压发展期间肾脏中线粒体O2利用ATP生产效率降低。作为加拿大合作者，莱顿和她的小组将开发计算模型，提供一个独特的定量和机制框架，使可测试的预测之间存在的复杂关系线粒体O2利用，能源生产，和氧化应激在肾脏盐敏感性高血压的发展。将为男性和女性开发单独的模型，以研究这些过程中的性别差异。因此，可以确定新的性别特异性治疗靶点。