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

Fatima Zohra Khamissi1, Liang Ning1, Eirini Kefaloyianni1

  • 1Washington University School in St. Louis School of Medicine, 660 S Euclid Avenue, St. Louis, MO 63110, USA.

Science Advances
|February 25, 2022
PubMed

Insights

Kidney injury can cause lung injury through a mediator called osteopontin (OPN). Inhibiting OPN prevents this secondary organ damage, offering potential new treatments for acute kidney injury and acute lung injury.

Area of Science:

  • Nephrology
  • Pulmonology
  • Immunology
  • Molecular Biology

Background:

  • Secondary organ injury following tissue damage is a significant clinical challenge.
  • The precise mechanisms and mediators driving interorgan crosstalk, such as acute kidney injury (AKI) leading to acute lung injury (ALI), remain incompletely understood.

Purpose of the Study:

  • To identify novel mediators involved in interorgan crosstalk using AKI-induced ALI as a model.
  • To elucidate the role of kidney-derived factors in triggering lung injury after AKI.

Main Methods:

  • Single-cell RNA sequencing of kidney and lung tissues in a mouse model of AKI.
  • Ligand-receptor pairing analysis to identify cross-organ signaling pathways.
  • Pharmacological and genetic inhibition of identified mediators.
  • Kidney transplantation experiments using wild-type and knockout mice.
  • Measurement of serum osteopontin levels in AKI patients.

Main Results:

  • Kidney-released circulating osteopontin (OPN) was identified as a key mediator of AKI-ALI.
  • OPN from kidney tubule cells induced lung endothelial leakage, inflammation, and respiratory failure.
  • Inhibition of OPN, either pharmacologically or genetically, ameliorated AKI-ALI.
  • Transplantation of ischemic kidneys lacking OPN did not induce ALI, confirming OPN's necessity.
  • Elevated serum OPN levels in AKI patients correlated with kidney injury severity.

Conclusions:

  • Kidney-derived OPN is a critical mediator of lung injury following AKI.
  • Targeting OPN presents a potential therapeutic strategy for AKI-ALI and multiorgan failure.
  • Cross-organ ligand-receptor analysis is a feasible approach for discovering interorgan communication mediators.

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