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.

肾小管重新吸收 >99% 的肾小球滤液，部分是通过需要能量利用的主动转运过程。驱动管状运输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，而这反过来又需要持续的 ATP 生成速率，主要通过有氧过程。因此，肾脏的氧气消耗率仅次于心脏。线粒体密度最大的地方是近端肾小管和粗的升肢。尽管肾脏代谢非常重要，并且人们广泛认识到细胞代谢在其他疾病中的作用，但相对较少的研究关注高血压发展中的这些方面。然而，最近对人类和动物模型的研究引起了人们对肾底物和能量代谢的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仍然很大程度上未知，并且大多数研究主要是基于描述性的。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，这些实验将为定量了解氧化应激发展和肾脏中 ATP 生产线粒体 O2 利用效率降低的细胞和分子机制提供所需的数据。在盐敏感性高血压的发展过程中。作为加拿大合作者，Layton 和她的团队将开发计算模型，该模型将提供独特的定量和机制框架，从而能够对盐发育过程中线粒体 O2 利用、能量产生和肾脏氧化应激之间存在的复杂关系进行可测试的预测。敏感高血压。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。由此可能会出现新的、针对性别的治疗靶点。