Cardiac dysfunction after ischemic AKI in mice

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Abstract The overall goal of this proposal is to determine the mechanisms by which acute kidney injury (AKI) leads to acute cardiac dysfunction. Clinically, AKI-mediated cardiac dysfunction is known as cardiorenal syndrome type 3 (CRS3). The mechanisms underpinning CRS3 are not well understood and few plausible mediators of CRS3 have been identified. We recently demonstrated that ischemic AKI causes cardiac dysfunction in mice which was associated with a 50% reduction in cardiac ATP levels. Thus, cardiac energy metabolism and production is impaired during AKI and is a fundamental characteristic of CRS3. To identify mediators of CRS3, we examined plasma and cardiac metabolites. We expected to identify increased levels of circulating metabolites that might affect cardiac energy metabolism. Rather, we found that numerous metabolites necessary to maintain cardiac energy production and anti-oxidant defense were deficient in the plasma and heart after AKI, including over a dozen amino acids and the anti-oxidant glutathione. During cardiac stress, amino acids are essential substrates for ATP production. Glutamine is particularly important since it can be metabolized to substrates for both ATP and glutathione synthesis. Glutathione is the most abundant anti-oxidant in the heart and is critical to maintain normal energy production since excess reactive oxygen species (ROS) impairs mitochondrial function and inhibits oxidative phosphorylation (OXPHOS). OXPHOS occurs within mitochondria and is normally the major mechanism of cardiac ATP production. Our preliminary data demonstrate that during AKI: 1) cardiac mitochondrial function and OXPHOS are impaired, 2) cardiac superoxide (O2●-, an ROS) is significantly increased, 3) glutamine significantly increases cardiac ATP and reduces O2●-. Based on these data, our overall hypothesis is that the deficiency of energy substrates and glutathione precursors during AKI results in increased reactive oxygen species, reduced OXPHOS, reduced ATP production, and cardiac dysfunction. We have 3 Aims. Aim 1: Determine the effect of AKI on cardiac energy metabolism via metabolic flux analysis. Aim 2: Determine the mechanisms by which glutamine improves cardiac ATP production after AKI, in vivo, with the hypothesis that glutamine will reduce cardiac O2●-, increase ATP production, and improve mitochondrial and cardiac function. Aim 3: Determine the substrates of glutamine metabolism that improve cardiac ATP production after AKI, ex vivo, with the hypothesis that metabolism to glutathione is the primary mechanism of glutamine benefit. Since the complications of AKI have long been considered to be due to the accumulation of metabolic wastes and other substances that may be removed by dialysis for patient benefit, our overall hypothesis that substrate deficiency is a mechanisms of harm is a paradigm shift that challenges one of the most fundamental notions in nephrology and will have wide ranging implications regarding the care of patients with AKI, particularly regarding dialysis.