Renal Oxygenation and Mitochondrial Function in the in the Pathophysiology of Kidney Disease
Project Number2I01BX002175-05A2
Former Number2I01BX002175-05A1
Contact PI/Project LeaderSINGH, PRABHLEEN
Awardee OrganizationVA SAN DIEGO HEALTHCARE SYSTEM
Description
Abstract Text
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.
Public Health Relevance Statement
Chronic kidney disease (CKD) kills almost 90,0000 Americans every year, more than the death rate with cancers
of the breast and prostate combined. While more than 20 million U.S. adults suffer from CKD, the rates are
higher among Veterans. Moreover, Veterans with CKD also have much higher rates of other diseases such as
diabetes, high blood pressure, and heart disease. Some forms of injury to the kidney can be temporary, referred
to as acute kidney injury (AKI). However, recent research suggests that even AKI can cause CKD by itself. When
AKI occurs in the setting of CKD, it can worsen CKD to complete kidney failure as has been shown in several
studies in the Veteran population. CKD itself can impede the recovery from AKI. The specific mechanisms that
lead to these poor outcomes are not well known. The main goal of this project is to identify the specific pathways
that cause the interactions between AKI and CKD and lead to worsening of kidney disease. The results of these
studies could lead to early interventions and medications to improve the health of the Veteran population.
No Sub Projects information available for 2I01BX002175-05A2
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