Renal Oxygenation and Mitochondrial Function in the in the Pathophysiology of Kidney Disease

点击翻译按钮获取中文摘要

Acute kidney injury (AKI) and chronic kidney disease (CKD) mutually reinforce each other leading to poor outcomes in patients. This is a significant issue in the Veteran population in whom the incidences of both AKI and CKD are increased. Moreover, both conditions are associated with significant comorbidities including diabetes, HTN and cardiovascular disease and high mortality. After AKI, patients are at increased risk of progression to CKD. Meanwhile, CKD predisposes patients to AKI and frequently impedes recovery from it. Despite several clinical studies identifying these harmful interactions, the underlying mechanisms remain elusive. This proposal directly addresses the gap in knowledge of the mechanisms by which CKD negatively impacts recovery from AKI and proposes to advance novel therapeutics for this important problem effecting the health of the Veteran population. Typically, kidney proximal tubules support high levels of transport fueled by mitochondrial oxidative phosphorylation (OXPHOS) with limited glycolytic capacity. However, preliminary data demonstrates significant alterations in proximal tubular metabolism with increased glycolysis in the subtotal nephrectomy model of CKD. Prior data implicate a role for diminished activity of AMP-Kinase (AMPK) pathway, which is a central energy sensor and regulator of metabolism in cells. Additionally, alterations in tubular metabolism and impaired mitochondrial function are also seen after AKI. How tubular metabolism and transport evolve after AKI and how pre-existing changes in these factors impact tubular recovery is not known and will be addressed in this proposal. The specific aims of the project include investigating the role of AMPK in proximal tubular reprogramming in CKD and AKI and how pre-existing changes in tubular metabolism and transport impact recovery from AKI. The proposed work will be accomplished utilizing novel methodologies to assess tubular metabolism combined with contemporary molecular methods and classical, physiological techniques such as renal micropuncture to provide mechanistic insights into proximal tubular transport and its relevance to tubular metabolism (oxidative and glycolytic) in recovery from AKI in CKD. Validation of pertinent findings in other injury models and translational relevance to clinical disease will also be assessed. These investigations will provide important and novel insights into the early mechanisms of disease progression and identify treatment strategies that can be employed early to prevent the usual course of disease progression. The understanding obtained from these investigations will be valuable beyond the model studied given the universal implications of cellular metabolism and mitochondrial dysfunction in various pathophysiological conditions in several organs. Importantly, the high clinical relevance and direct relevance to the health of the Veteran population lend significant impact to the proposed research.