Mitochondrial Bioenergetics in the Kidney: Sex-specific Computational Modelling

肾小管重新吸收99%的肾小球滤液，部分通过主动运输过程，需要能量利用。驱动管状转运的跨细胞浓度梯度主要是由Na+-K+-ATP酶泵建立的，它使用ATP水解作为能量来源，反过来，这需要持续的ATP生成速率，主要是通过有氧过程。因此，肾脏的耗氧率仅次于心脏。线粒体密度最大的是近端小管和粗大的升肢。尽管肾脏代谢的重要性和细胞代谢在其他疾病中的作用被广泛认识，但相对较少的研究关注这些方面在高血压的发展。然而，最近在人类和动物模型中的研究激起了人们对肾底物和能量代谢改变在高血压中可能起作用的兴趣，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，而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，该实验将为定量理解盐敏感性高血压发展过程中氧化应激发展的细胞和分子机制提供所需的数据，并降低肾脏线粒体对ATP生产的O2利用效率。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，使可测试的预测存在于盐敏感性高血压发展过程中线粒体O2利用、能量产生和肾脏氧化应激之间的复杂关系。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，可能会出现新的和性别特异性治疗靶点的鉴定。

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.