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

描述（由申请人提供）： 这是一份为期5年的提案，旨在将候选人培养为肾脏生理学和病理生理学竞技场的医生科学家。它将允许在基本生理方法的研究培训的延长期，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，并指导了许多学员取得成功的学术生涯。UCSD为年轻的研究人员提供了一个理想的培养环境，有机会与肾脏科内外许多成熟的研究人员进行互动和合作。 在慢性肾病（CKD）中，剩余肾单位的适应性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，肾脏具有预定义和有限的物理因素（肾小球和肾小管），可以改变这些因素以维持GFR。此外，预先存在的环境的变化可能会影响对后续损伤的反应。我们在CKD模型大鼠的早期肾大部切除术（CKD）中观察到缺血事件后GFR下降的相对抵抗力。我们对早期肾脏损伤的生理、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，肾单位功能的适应性变化包括肾小管肾小球反馈（TGF）反应的缺失，这可以减少正常情况下GFR的下降。其他肾小球和肾小管因素，但尚未检查，也可能是重要的。最后，体内预处理可提供对近端小管细胞的抗性。使用显微穿刺和分子生物学技术，我们建议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包容性的网络结构，确定早期GFR对IR的相对不敏感性是由于TGF、物理因素和其他体液因素的差异所致的程度。2)确定细胞抵抗缺血的潜在机制，以及缺氧诱导因子及其下游效应在这种反应中的作用。这将是第一次详细分析慢性肾脏病急性肾损伤的机制。

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.