Pathophysiology of Early Chronic Kidney Disease: Response to Ischemia-Reperfusion

早期慢性肾脏病的病理生理学：对缺血再灌注的反应

• 批准号: 8511614
• 负责人: Prabhleen Singh
• 金额: $ 15.11万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8511614
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Angiotensin II; Cells; Chronic; Chronic Kidney Failure; Data; Development; Environment; Event; Feedback; Filtration; Fostering; Functional disorder; Future; Goals; Health; Hypoxia Inducible Factor; Individual; Injury; Injury to Kidney; Investigation; Ischemia; Kidney; Light; Mediating; Mentors; Metabolic; Methods; Micropuncture; Modeling; Molecular; Molecular Biology Techniques; Nephrectomy; Nephrology; Nephrons; Physicians; Physiological; Physiology; Play; Rattus; Relative (related person); Renal function; Reperfusion Therapy; Research Design; Research Personnel; Research Training; Residual state; Resistance; Role; Scientist; Staging; Testing; Tubular formation; career; in vivo; insight; public health relevance; response; salt balance; theories; therapeutic target

DESCRIPTION (provided by applicant): This is a 5-year proposal for the development of the candidate as a physician scientist in the arena of renal physiology and pathophysiology. It will allow an extended period of research training in basic physiologic methods to accomplish this goal. The mentor, Dr. Blantz, is a well-recognized leader in the field of renal physiology and has mentored numerous trainees to achieve successful academic careers. UCSD provides an ideal fostering environment for young investigators with opportunities to interact and collaborate with many well-established investigators within and outside the Division of Nephrology. In chronic kidney disease (CKD), adaptations in remaining nephrons help maintain the primary functions of the kidney i.e. filtration and salt balance in the earlier stages. In the face of successive nephron loss, the kidney has pre-defined and limited sets of physical factors (glomerular and tubular) that can be altered to maintain GFR. In addition a change in the pre-existing environment can influence the response to subsequent injury. A relative resistance to decline in GFR has been observed by us after an ischemic event in early subtotal nephrectomy (STN) in rat, a model of CKD. Our investigations of the physiologic, metabolic and molecular milieu in early STN provide valuable insights into the overall response of the kidney to injury. At baseline, adaptations in nephron function include an absence of tubuloglomerular feedback (TGF) response, which can curtail the decline in GFR seen normally. Other glomerular and tubular factors, yet unexamined, could also be important. Finally in vivo preconditioing can afford resistance to proximal tubuar cells. Using micropuncture and molecular biology techniques we propose to provide useful mechanistic information. The specific aims include: 1) Determine the degree to which the relative insensitivity of GFR to IR in the early stage is due to differences in TGF, physical factors, and other humoral factors using a simple, yet inclusive, network construct applied to micropuncture data. 2) Determine the underlying mechanisms of cellular resistance to ischemia in STN and the role of hypoxia inducible factor and its downstream effects in this response. These will be the first detailed analysis of the mechanisms of acute kidney injury in the presence of CKD.

描述（由申请人提供）： 这是一项为期 5 年的提案，旨在培养候选人成为肾脏生理学和病理生理学领域的医师科学家。它将允许在基本生理学方法方面进行长期的研究培训以实现这一目标。导师Blantz博士是肾脏生理学领域公认的领导者，指导了众多学员取得成功的学术生涯。加州大学圣地亚哥分校为年轻研究人员提供了理想的培养环境，让他们有机会与肾脏病学部门内外的许多知名研究人员进行互动和合作。 在慢性肾脏病 (CKD) 中，剩余肾单位的适应有助于维持肾脏的主要功能，即早期阶段的过滤和盐平衡。面对连续的肾单位损失，肾脏具有预先定义的和有限的物理因素（肾小球和肾小管），可以改变这些因素以维持 GFR。此外，先前环境的变化也会影响对后续伤害的反应。我们在 CKD 模型大鼠早期肾次全切除术 (STN) 发生缺血事件后观察到 GFR 下降的相对抵抗力。我们对早期 STN 的生理、代谢和分子环境的研究为肾脏对损伤的整体反应提供了有价值的见解。 在基线时，肾单位功能的适应包括肾小球反馈（TGF）反应的缺失，这可以抑制正常情况下出现的 GFR 下降。其他尚未检查的肾小球和肾小管因素也可能很重要。最后，体内预处理可以提供对近端肾小管细胞的抵抗力。我们建议使用微穿刺和分子生物学技术提供有用的机制信息。具体目标包括： 1) 使用应用于微穿刺数据的简单但具有包容性的网络结构，确定早期阶段 GFR 对 IR 的相对不敏感程度是由于 TGF、物理因素和其他体液因素的差异造成的。 2)确定细胞抵抗STN缺血的潜在机制以及缺氧诱导因子的作用及其在该反应中的下游效应。这将是对 CKD 情况下急性肾损伤机制的首次详细分析。