Identification of kidney injury–released circulating osteopontin as causal agent of respiratory failure

Abstract

Tissue injury can drive secondary organ injury; however, mechanisms and mediators are not well understood. To identify interorgan cross-talk mediators, we used acute kidney injury (AKI)–induced acute lung injury (ALI) as a clinically important example. Using kidney and lung single-cell RNA sequencing after AKI in mice followed by ligand-receptor pairing analysis across organs, kidney ligands to lung receptors, we identify kidney-released circulating osteopontin (OPN) as a novel AKI-ALI mediator. OPN release from kidney tubule cells triggered lung endothelial leakage, inflammation, and respiratory failure. Pharmacological or genetic OPN inhibition prevented AKI-ALI. Transplantation of ischemic wt kidneys caused AKI-ALI, but not of ischemic OPN–global knockout kidneys, identifying kidney-released OPN as necessary interorgan signal to cause AKI-ALI. We show that OPN serum levels are elevated in patients with AKI and correlate with kidney injury. Our results demonstrate feasibility of using ligand-receptor analysis across organs to identify interorgan cross-talk mediators and may have important therapeutic implications in human AKI-ALI and multiorgan failure.

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

“…In a very recent study in mice, nephrectomy did not produce significant changes in lung alveolar wall oedema or accumulation of lung immune cells. Also, in this study, IL‐6 or other cytokine levels were not determined in detail after nephrectomy [68]. The reasons for these discrepancies are not clear, but it is theoretically possible that even though inbred C57Bl6 mice were used in most of these studies, drift in their genetic background may occur over time and could play a role, or differences in surgical technique or anaesthetic protocols used.…”

“…OPN, similar to HMGB1, appears to represent such a mediator; in contrast to, for example, IL‐6, IL‐8 or TNF which are hardly expressed in the normal kidney and require upregulation by injury. A recent study that applied single‐cell RNA sequencing (scRNAseq) for the first time to AKI–ALI identified OPN released from the injured kidney after ischaemic AKI as a key mediator of lung endothelial leakage and inflammation in AKI–ALI [68]. Using kidney and lung scRNAseq after AKI or sham operation in mice (24 h after operation) followed by computational ligand‐receptor pairing analysis across organs, kidney ligands to cognate lung receptors, kidney osteopontin was predicted to act as an AKI–ALI mediator and interact with CD44 receptors in lung cells.…”

“…These results predict a potential role of these immune cells as targets of OPN in the lung. Finally, OPN serum levels in mice were strongly positively correlated with severity of kidney injury [68].…”

“…In human serum samples, OPN was strongly elevated in AKI patients but not in chronic kidney disease (CKD) patients and correlated with kidney injury [68]. A study in ICU patients reported as primary outcome that persistently elevated OPN serum levels correlate with increased mortality in multiorgan failure.…”

“…[8]). They appear to have a role in early AKI–ALI, as they invade the lung already 1–2 h after AKI [68,128]. However, no study, to date, has assessed the effect of neutrophil depletion on AKI–ALI.…”