Lung metabolomics after ischemic acute kidney injury reveals increased oxidative stress, altered energy production, and ATP depletion

Abstract

Acute kidney injury (AKI) is a complex disease associated with increased mortality that may be due to deleterious distant organ effects. AKI associated with respiratory complications, in particular, has a poor outcome. In murine models, AKI is characterized by increased circulating cytokines, lung chemokine upregulation, and neutrophilic infiltration, similar to other causes of indirect acute lung injury (ALI)(e.g., sepsis). Many causes of lung inflammation are associated with a lung metabolic profile characterized by increased oxidative stress, a shift towards the use of other forms of energy production, and/or a depleted energy state. To our knowledge, there are no studies that have evaluated pulmonary energy production and metabolism after AKI. We hypothesized that based on the parallels between inflammatory acute lung injury and AKI-mediated lung injury, a similar metabolic profile would be observed. Lung metabolomics and ATP levels were assessed 4 hours, 24 hours, and 7 days after ischemic AKI in mice. Numerous novel findings regarding the effect of AKI on the lung were observed including 1) increased oxidative stress, 2) a shift toward alternate methods of energy production, and 3) depleted levels of ATP. The findings in this report bring to light novel characteristics of AKI-mediated lung injury and provide new leads into the mechanisms by which AKI in patients predisposes to pulmonary complications.

Chrysosplenol D protects mice against LPS-induced acute lung injury by inhibiting oxidative stress, inflammation, and apoptosis via TLR4-MAPKs/NF-κB signaling pathways

“…In recent years, an increasing number of studies have demonstrated that the development of ALI is related to inflammation, oxidative stress, apoptosis, and cellular immunity. [16][17][18][19] However, mortality due to ALI continues to be high. There are many published reports on the activity of natural products to treat ALI.…”

Betel Nut Chewing Was Associated with Obstructive Lung Disease in a Large Taiwanese Population Study

“…In addition, a significant decrease in renal function was also observed in patients with FEV1/FVC < 70%. Crosstalk between COPD and renal function can attribute to a complex mechanism containing inflammation [37,38]. The inflammatory mediators affect both lung and renal function [39].…”

Interorgan crosstalk mechanisms in disease: the case of acute kidney injury‐induced remote lung injury

“…Recent data suggest that AKI induces metabolic alterations, for example, in the heart [138] or lung [139,140], possibly implicating metabolites in AKI–ALI. In mice subjected to bilateral ischaemia reperfusion injury, the metabolome of the remotely injured lung was examined by mass spectrometry 4 h after bilateral kidney ischaemia reperfusion injury and compared to sham operation.…”

“…Measurements of lung inflammation, lung MPO activity and lung KC/CXCL1 (‘IL8’) expression were elevated and peaked at 4 h after AKI, and lung ATP depletion had a nadir at 4 h. Lung ATP is to 80% produced by mitochondrial respiration (oxidative phosphorylation) and its depletion reports oxygen poor states and/or mitochondrial dysfunction. The most significant changes in the metabolome were detected at 24 h. Beyond ATP depletion, the analysis revealed evidence of alternative energy production and increased oxidative stress in the lung [140]. Whether the observed metabolic changes and/or altered metabolites act as AKI–ALI mediators and have a direct role in establishing or driving AKI–ALI or whether they are a result of interorgan crosstalk driven by other AKI–ALI mediators that signal between the kidney or extrarenal organs and the lung is unresolved to date.…”