Metabolomics assessment reveals oxidative stress and altered energy production in the heart after ischemic acute kidney injury in mice

Abstract

Acute kidney injury (AKI) is a systemic disease associated with widespread effects on distant organs, including the heart. Normal cardiac function is dependent on constant ATP generation, and the preferred method of energy production is via oxidative phosphorylation. Following direct ischemic cardiac injury, the cardiac metabolome is characterized by inadequate oxidative phosphorylation, increased oxidative stress, and increased alternate energy utilization. We assessed the impact of ischemic AKI on the metabolomics profile in the heart. Ischemic AKI was induced by 22 minutes of renal pedicle clamping, and 124 metabolites were measured in the heart at 4 hours, 24 hours, and 7 days post-procedure. Forty-one percent of measured metabolites were affected, with the most prominent changes observed 24 hours post-AKI. The post-AKI cardiac metabolome was characterized by amino acid depletion, increased oxidative stress, and evidence of alternative energy production, including a shift to anaerobic forms of energy production. These metabolomic effects were associated with significant cardiac ATP depletion and with echocardiographic evidence of diastolic dysfunction. In the kidney, metabolomics analysis revealed shifts suggestive of energy depletion and oxidative stress, which were reflected systemically in the plasma. This is the first study to examine the cardiac metabolome after AKI, and demonstrates that effects of ischemic AKI on the heart are akin to the effects of direct ischemic cardiac injury.

Distant organ dysfunction in acute kidney injury

“…Notes. 64 Importantly, these metabolomic effects were associated with significant cardiac ATPase depletion and with echocardiographic evidence of diastolic dysfunction. AKI = acute kidney injury; ↓ = decreased; IL = interleukin; ↑ = increased; RAAS = renin-angiotensinaldosterone system; TNF = tumour necrosis factor immunoreactive IL-1 and TNF-α and intercellular adhesion molecule-1 mRNA expression in the heart may explain the observed impaired cardiac function, endothelial dysfunction, increased cardiac myeloperoxidase activity (consistent with leucocyte infiltration in the heart) and myocyte apoptosis (evident with TUNEL staining).…”

“…Interactions between the kidney and heart in cardiorenal syndrome type 3 causing acute cardiac dysfunction. 64 Finally, fibroblast growth factor-23 has been identified to be a predictor of cardiovascular disease in patients with CKD by inducing cardiac left ventricular hypertrophy independent of blood pressure. 60,61 Interestingly, apoptosis was not observed following bilateral nephrectomy, suggesting that renal ischaemia, but not uraemia, is required for the associated apoptosis.…”

“…63 Recently, a study demonstrated that the post-ischaemic AKI cardiac metabolome in mice was characterized by amino acid depletion, increased oxidative stress and evidence of alternative energy production, including a shift to anaerobic forms of energy production. 64 Importantly, these metabolomic effects were associated with significant cardiac ATPase depletion and with echocardiographic evidence of diastolic dysfunction. 64 Finally, fibroblast growth factor-23 has been identified to be a predictor of cardiovascular disease in patients with CKD by inducing cardiac left ventricular hypertrophy independent of blood pressure.…”

“…64 Importantly, these metabolomic effects were associated with significant cardiac ATPase depletion and with echocardiographic evidence of diastolic dysfunction. 64 Finally, fibroblast growth factor-23 has been identified to be a predictor of cardiovascular disease in patients with CKD by inducing cardiac left ventricular hypertrophy independent of blood pressure. 65 Interestingly, this effect was attenuated by the administration of a fibroblast growth factor-receptor blocker in a rat model of CKD 65 or by the administration of Klotho in mouse models of CKD.…”

Leaky gut potentially leads to bacterial/endotoxin translocation in a rat model of non-ischemic acute kidney injury

“…Bilateral nephrectomy (BNx) is a model of non-ischemic AKI [11][12] that is used to examine the deleterious systemic effects of renal dysfunction without taking into account the confounding effects, such as non-renal organ injury or accelerated systemic oxidative stress, which are commonly involved in ischemic AKI [13][14] . In this study, BNx model was used to determine the unique role of the kidney and AKI in promoting bacterial/endotoxin translocation and the mechanism behind it?…”