Unraveling Kidney Physiology, Pathophysiology & Therapeutics: A Modeling Approach

 描述（由申请人提供）：糖尿病和高血压是发生慢性肾脏疾病（CKD）的主要风险因素。尽管进行了大量的研究，但对肾脏缺氧和CKD的潜在机制仍然知之甚少。这种困难可能归因于数百万肾小管和血管之间的复杂相互作用，这些肾小管和血管构成了肾脏综合功能的基础，但仍有待充分表征。我们以前已经开发了大鼠肾脏的计算模型，这些模型代表了复杂的相互作用，我们的目标是扩展这些模型，并进行模拟，以提供对肾脏健康和疾病的见解。建议的项目包括：（I）开发一个详细的和多尺度的计算模型的综合大鼠肾功能，并使用该模型来检查肾功能和髓质氧合的关键决定因素。将进行功能敲除和肾单位丧失的模拟，以确定：在维持整体关键肾功能的同时，必须保留或应抑制哪些必要的肾单位结构和功能，以维持或增加脆弱外髓质中的氧平衡？(II)模拟并深入了解高血压和糖尿病患者肾缺氧的病理生理学和治疗学。高血压和糖尿病对肾小管系统产生独特的影响，增加肾脏耗氧量。将进行模型模拟，以研究影响肾内氧分压（PO 2）的因素，特别是在脆弱的外髓质中，包括高血压诱导的Na+转运向更远端和效率较低的肾单位节段的转移、氧化应激升高、糖尿病诱导的超滤和肾小管肥大和超重吸收。我们将模拟和研究当前和新型治疗方法的有效性，并寻求回答以下问题：如何增加高血压患者的Na+排泄，同时限制对其他肾功能的影响并保持髓质氧合？在糖尿病中，抑制Na+-葡萄糖共转运对肾脏NaCl转运和O2需要量的影响是什么？减压操作在多大程度上增加髓质PO 2并保护肾脏？(III)进行实验研究以评估钠-葡萄糖协同转运蛋白（SGLT）抑制对肾脏的影响。通过SGLT 2抑制葡萄糖沿近端小管的沿着重吸收是降低糖尿病血糖水平的新方法。我们将对小鼠进行实验，以确定：SGLT 2抑制是否会增强脆弱下游肾单位节段的Na+转运并增加外髓缺氧？对晚期近端小管沿着SGLT 1的额外抑制（限制Na+）是否有任何贝内 沿着该节段的葡萄糖重吸收，但可能进一步增加厚上升肢体Na+转运？SGLT抑制促进缺血再灌注损伤还是损害恢复？在完成这些研究时，我们将获得对正常肾脏中肾功能和髓质氧合的关键决定因素的新见解，并确定它们在高血压和糖尿病到CKD的途径中的潜在相关性。

 DESCRIPTION (provided by applicant): Diabetes and hypertension are major risk factors for developing chronic kidney diseases (CKD). Despite intense research, the mechanisms that underlie the pathways to renal hypoxia and CKD remain poorly under- stood. That difficulty may be attributable to the complex interplay among the millions of renal tubules and vessels that forms the basis for the integrative function of the kidney but that remains to be fully characterized. We have previously developed computational models of the rat kidney that represent the complex interactions, and we aim to extend those models and to conduct simulations that will provide insights into the kidney in health and disease. The proposed project includes (I) To develop a detailed and multiscale computational model of integrative rat kidney function, and to use that model to examine key determinants of kidney function and medullary oxygenation. Simulations of functional knockout and nephron loss will be conducted to determine: What are the necessary nephron structures and functions that must be preserved or should be inhibited to maintain or increase oxygen balance in the vulnerable outer medulla, while maintaining overall key kidney functions? (II) To simulate and gain insights into the pathophysiology and therapeutics of renal hypoxia in hypertension and diabetes. Hypertension and diabetes induce unique effects on the tubular system that increases kidney oxygen consumption. Model simulations will be conducted to investigate factors that impact intrarenal oxygen tension (PO2), particularly in the vulnerable outer medulla, including hypertension-induced shift in Na+ transport to the more distal and less efficient nephron segments, elevated oxidative stress, diabetes-induced hyperfiltration and tubular hypertrophy and hyper-reabsorption. We will simulate and investigate the effectiveness of current and novel therapeutic treatments and seek to answer questions like: How can one increase Na+ excretion in hypertension while limiting effects on other kidney functions and preserve medullary oxygenation? In diabetes, what is the influence of inhibiting Na+-glucose cotransport on renal NaCl transport and O2 requirement? To what extent do pressure reduction maneuvers increase medullary PO2 and protect the kidney? (III) To conduct experimental studies to assess the renal effects of sodium-glucose cotransporter (SGLT) inhibition. Inhibiting glucose reabsorption along the proximal tubule via SGLT2 is a novel approach for lower blood glucose level in diabetes. We will perform experiments on mice to determine: Does SGLT2 inhibition enhance Na+ transport of vulnerable downstream nephron segments and increase outer medullary hypoxia? Is there any benefit in the additional inhibition of SGLT1 along the late proximal tubule, which limits Na+ glucose reabsorption along that segment, but may further increase thick ascending limb Na+ transport? Does SGLT inhibition facilitate ischemia- reperfusion injury or impair the recovery? At the completion of these studies, we would have gained new insights into the key determinants of kidney function and medullary oxygenation in the normal kidney, and determined their potential relevance in the pathways from hypertension and diabetes to CKD.