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

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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.