Unraveling Kidney Physiology, Pathophysiology & Therapeutics: A Modeling Approach

解开肾脏生理学、病理生理学

• 批准号: 9264525
• 负责人: Anita Layton
• 金额: $ 34.19万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9264525
• 关键词: Acid-Base Equilibrium; Adult; Affect; Animal Experiments; Attenuated; Blood Glucose; Blood Vessels; Blood flow; Carrier Proteins; Chronic Kidney Failure; Complex; Computer Simulation; Diabetes Mellitus; Disease; Distal; Economic Burden; Effectiveness; Electrolytes; Equilibrium; Excretory function; Expenditure; FDA approved; Functional disorder; Gluconeogenesis; Glucose; Goals; Health; Homeostasis; Hypertension; Hypertrophy; Hypoxia; Impairment; Ischemia; Kidney; Knock-out; Lead; Limb structure; Medicare; Metabolism; Micropuncture; Modeling; Mus; Natriuresis; Nephrons; Operative Surgical Procedures; Organ; Oxidative Stress; Oxygen; Oxygen Consumption; Pathway interactions; Patients; Physiology; Pimonidazole; Population; Prevention strategy; Public Health; Rattus; Recovery; Regional Blood Flow; Renal function; Renal tubule structure; Reperfusion Injury; Reperfusion Therapy; Research; Risk Factors; Rodent; Rodent Model; Safety; Sodium; Staining method; Stains; Structure; Structure-Activity Relationship; System; Techniques; Therapeutic; Thick; Transport Process; Tubular formation; United States; Urine; Vascular blood supply; Vasodilation; Work; diabetic; effective therapy; experimental study; glucose uptake; hemodynamics; inhibitor/antagonist; insight; kidney vascular structure; models and simulation; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pressure; protein transport; public health relevance; renal hypoxia; simulation; treatment strategy

 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.

 描述(申请人提供)：糖尿病和高血压是发展慢性肾脏疾病(CKD)的主要危险因素。尽管进行了密集的研究，但肾脏缺氧和慢性肾脏病的机制仍然不太清楚。这种差异可能归因于数以百万计的肾小管和血管之间复杂的相互作用，这些相互作用构成了肾脏综合功能的基础，但这一点仍有待充分表征。我们之前已经开发了代表复杂相互作用的大鼠肾脏的计算模型，我们的目标是扩展这些模型，并进行模拟，以提供对肾脏在健康和疾病中的见解。建议的项目包括(I)开发一个详细的多尺度综合大鼠肾功能的计算模型，并使用该模型来研究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丢失的模拟，以确定：在维持整体关键肾功能的同时，必须保留或应该抑制哪些必要的肾单位结构和功能，以维持或增加脆弱的外髓质中的氧平衡？(Ii)模拟和了解高血压和糖尿病患者肾脏缺氧的病理生理学和治疗方法。高血压和糖尿病会对肾小管系统产生独特的影响，从而增加肾脏的氧气消耗。模型模拟将被用来研究影响肾内氧分压(PO2)的因素，特别是在脆弱的外髓，包括高血压引起的Na+转运到更远和更不有效的fi肾单位段，氧化应激升高，糖尿病引起的fi高渗漏以及肾小管肥大和重吸收。我们将模拟和研究当前和新的治疗方法的有效性，并寻求回答以下问题：如何在限制对其他肾功能的影响的同时增加高血压患者的Na+排泄，并保护髓质氧合？在糖尿病患者中，抑制Na+-葡萄糖共转运对肾脏盐分转运和氧气需求有何影响？fl。降压手法在多大程度上增加了髓质的PO2并保护了肾脏？(Iii)进行实验研究，以评估钠-葡萄糖共转运体(SGLT)抑制对肾脏的影响。通过SGLT2抑制近端小管的葡萄糖重吸收是降低糖尿病患者血糖水平的一种新方法。我们将在小鼠身上进行实验，以确定：SGLT2抑制是否增强了脆弱的下游肾单位节段的Na+转运，并增加了外髓缺氧？在限制Na+的近曲小管晚期对SGLT1的额外抑制中是否有任何有益的fit 葡萄糖沿该节段重吸收，但可能进一步增加粗大的上肢Na+转运？抑制SGLT是促进缺血再灌注损伤还是损害其恢复？在这些研究完成后，我们将对正常肾脏中肾功能和髓质氧合的关键决定因素获得新的见解，并确定它们在高血压和糖尿病到CKD的通路中的潜在相关性。