Altered lung metabolism and mitochondrial DAMPs in lung injury due to acute kidney injury

Mark Hepokoski, Jing Wang, Kefeng Li, Ying Li, Purva Gupta, Tina Mai, Alex Moshensky, Mona Alotaibi, Laura E. Crotty Alexander, Atul Malhotra, Prabhleen Singh

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

Acute respiratory distress syndrome (ARDS) is a common cause of mortality in patients with acute kidney injury (AKI). Inflammatory crosstalk from the kidney to the lung has been shown to contribute to lung injury after AKI, but anti-inflammatory therapies have not been proven beneficial in human studies. Recently, AKI was shown to alter mitochondria and related metabolic pathways in the heart, but the impact of AKI on lung metabolism has not been investigated to our knowledge. In this study, we evaluated the metabolomic profile of the lung following renal ischemia and reperfusion to identify novel pathways that may be modifiable. We randomized C57BL/6 mice to 20 minutes of bilateral renal arterial clamping or sham operation under ketamine/xylazine anesthesia. At 4 hours after reperfusion, we found a significant increase in markers of lung injury, as well as significant metabolomic changes across lung, kidney, plasma and bronchoalveolar lavage fluid (BALF) compared to shams. Comparative analyses revealed that the fatty acid oxidation pathway was the most significantly altered metabolic pathway, a finding which is consistent with mitochondrial dysfunction systemically and in the lung. These metabolomic changes correlated with the extracellular accumulation of the mitochondrial damage associated molecular patterns (mtDAMPs), mitochondrial DNA (mtDNA) and transcription factor A, mitochondria (TFAM). Finally, we found that intraperitoneal injection of renal mtDAMPs caused metabolomic changes consistent with mitochondrial dysfunction in the lung in vivo. Mitochondrial function and mtDAMPs warrant further investigation as potential therapeutic targets in preventing lung injury because of AKI.

Original languageEnglish
Pages (from-to)L821-L831
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume320
Issue number5
DOIs
Publication statusPublished - May 2021
Externally publishedYes

Keywords

  • AKI
  • ARDS
  • Metabolomics
  • Mitochondria
  • MtDAMPs

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