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

描述(由申请人提供)： 这是一项为期5年的建议，旨在将候选人培养为肾脏生理学和病理生理学领域的内科科学家。它将允许在基本生理学方法方面进行较长时间的研究培训，以实现这一目标。这位导师布兰茨博士是肾脏生理学领域公认的领导者，曾指导过许多学员取得成功的学术生涯。加州大学圣迭戈分校为年轻研究人员提供了一个理想的培养环境，有机会与肾病科内外的许多知名研究人员互动和合作。 在慢性肾脏疾病(CKD)中，剩余肾单位的适应有助于维持肾脏的主要功能，即早期的滤过和盐平衡。面对连续的肾单位丢失，肾脏有预先定义的和有限的物理因素集(肾小球和肾小管)，可以改变这些因素来维持GFR。此外，预先存在的环境的改变可能会影响对后续伤害的反应。我们在CKD模型大鼠早期肾大部切除术(STN)中观察到了对GFR下降的相对抵抗。我们对早期STN的生理、代谢和分子环境的研究为了解肾脏对损伤的整体反应提供了有价值的见解。 在基线状态下，肾单位功能的适应包括肾小管小球反馈(TGF)反应的缺失，这可以减少正常情况下GFR的下降。其他尚未检测的肾小球和肾小管因素也可能很重要。最后，体内预适应可以抵抗近端肾小管上皮细胞。利用显微穿刺术和分子生物学技术，我们建议提供有用的机制信息。具体目标包括：1)使用一个简单但包容的网络结构应用于微穿孔数据，确定早期GFR对IR的相对不敏感程度是由于转化生长因子、物理因素和其他体液因素的差异所致。2)探讨STN细胞对缺血耐受的机制，以及缺氧诱导因子及其下游效应在此反应中的作用。这将是首次详细分析慢性肾脏病并发急性肾损伤的机制。 公共卫生相关性：慢性肾脏疾病是一个主要的健康问题，先前存在的慢性肾脏病引起的急性肾脏损伤越来越被认识到。当AKI发生在CKD的背景下时，它有重要的差异，我们的目标是定义这些差异。肾脏在早期阶段对损伤的反应有助于确定未来潜在的治疗靶点。

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. PUBLIC HEALTH RELEVANCE: Chronic kidney disease is a major health problem and acute kidney injury on pre-existing CKD is increasingly being recognized. There are important differences in AKI when it occurs on a background of CKD and it is our goal to define those differences. How the kidney responds to injury at an early stage can help in identifying potential therapeutic targets in the future.