Mitochondrial Bioenergetics in the Kidney: Sex-specific Computational Modelling

肾小管重吸收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。驱动肾小管转运的跨细胞浓度梯度主要由Na+-K+-ATPase泵建立，Na+-K+-ATPase泵利用ATP水解作为能量来源，这反过来又需要持续的ATP生成速度，主要是通过好氧过程。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上肢。尽管肾脏代谢的重要性和细胞代谢在其他疾病中的作用得到了广泛的认识，但相对较少的研究集中在这些方面在高血压的发展中。然而，最近在人类和动物模型上的研究已经激起了越来越多的兴趣，即肾脏底物和能量代谢的变化在高血压中可能起到的作用，尽管这些代谢紊乱的分子基础和相关性在很大程度上仍不清楚，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，这些实验将提供必要的数据，以定量了解在盐敏感型高血压发展过程中肾脏氧化应激和线粒体氧利用ATP生产效率下降的潜在细胞和分子机制。作为加拿大的合作者，Layton和她的团队将开发计算模型，该模型将提供一个独特的定量和机制框架，使能够对盐敏感型高血压发展过程中肾脏线粒体氧气利用、能量产生和氧化应激之间存在的复杂关系进行可测试的预测。将为男性和女性开发不同的模型，以研究这些过程中的性别差异。因此，识别新的和特定性别的治疗靶点可能会出现。

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.