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Acute kidney injury decreases pulmonary vascular growth and alveolarization in neonatal rat pups

Pediatric Research volume 94, pages 1308–1316 (2023)Cite this article

Abstract

Background

Acute kidney injury (AKI) is common in sick neonates and associated with poor pulmonary outcomes, however, the mechanisms responsible remain unknown. We present two novel neonatal rodent models of AKI to investigate the pulmonary effects of AKI.

Methods

In rat pups, AKI was induced surgically via bilateral ischemia-reperfusion injury (bIRI) or pharmacologically using aristolochic acid (AA). AKI was confirmed with plasma blood urea nitrogen and creatinine measurements and kidney injury molecule-1 staining on renal immunohistochemistry. Lung morphometrics were quantified with radial alveolar count and mean linear intercept, and angiogenesis investigated by pulmonary vessel density (PVD) and vascular endothelial growth factor (VEGF) protein expression. For the surgical model, bIRI, sham, and non-surgical pups were compared. For the pharmacologic model, AA pups were compared to vehicle controls.

Results

AKI occurred in bIRI and AA pups, and they demonstrated decreased alveolarization, PVD, and VEGF protein expression compared controls. Sham pups did not experience AKI, however, demonstrated decreased alveolarization, PVD, and VEGF protein expression compared to controls.

Conclusion

Pharmacologic AKI and surgery in neonatal rat pups, with or without AKI, decreased alveolarization and angiogenesis, producing a bronchopulmonary dysplasia phenotype. These models provide a framework for elucidating the relationship between AKI and adverse pulmonary outcomes.

Impact

  • There are no published neonatal rodent models investigating the pulmonary effects after neonatal acute kidney injury, despite known clinical associations.

  • We present two novel neonatal rodent models of acute kidney injury to study the impact of acute kidney injury on the developing lung.

  • We demonstrate the pulmonary effects of both ischemia-reperfusion injury and nephrotoxin-induced AKI on the developing lung, with decreased alveolarization and angiogenesis, mimicking the lung phenotype of bronchopulmonary dysplasia.

  • Neonatal rodent models of acute kidney injury provide opportunities to study mechanisms of kidney-lung crosstalk and novel therapeutics in the context of acute kidney injury in a premature infant.

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Fig. 1: Experimental Timeline.
Fig. 2: Acute kidney injury measurements.
Fig. 3: Lung morphometric measurements.
Fig. 4: Lung angiogenic measurements.
Fig. 5: Sex Differences Among Pulmonary Outcomes.
Fig. 6: Lung weights and body weights.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    Brianna M. Liberio

  2. Department of Pediatrics, Section of Pulmonary and Sleep Medicine, University of Colorado School of Medicine, Aurora, CO, USA

    Gregory Seedorf & Steven H. Abman

  3. Department of Pediatrics, Division of Pediatric Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA

    Danielle E. Soranno

  4. Department of Medicine, Division of Renal Medicine and Hypertension, University of Colorado School of Medicine, Aurora, CO, USA

    John R. Montford & Sarah G. Faubel

  5. Renal Section, Rocky Mountain Regional VA Medical Center, Aurora, CO, USA

    John R. Montford

  6. Department of Pediatrics, Section of Neonatology, University of Colorado School of Medicine, Aurora, CO, USA

    Andres Hernandez & Jason Gien

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  1. Brianna M. Liberio
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  2. Gregory Seedorf
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  3. Danielle E. Soranno
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  5. Sarah G. Faubel
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Contributions

B.M.L. provided substantial contributions to conception and design, acquisition of data, and analysis and interpretation of data; drafted the article; provided final approval of the version to be published. G.S. and J.G. provided substantial contributions to conception and design, acquisition of data, and analysis and interpretation of data; revised the article critically for important intellectual content; provided final approval of the version to be published. D.E.S., J.R.M., and S.G.F. provided substantial contributions to conception and design; revised the article critically for important intellectual content; provided final approval of the version to be published. A.H. provided substantial contributions to acquisition of data; revised the article critically for important intellectual content; provided final approval of the version to be published. S.H.A. revised the article critically for important intellectual content; provided final approval of the version to be published.

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Correspondence to Brianna M. Liberio.

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Liberio, B.M., Seedorf, G., Soranno, D.E. et al. Acute kidney injury decreases pulmonary vascular growth and alveolarization in neonatal rat pups. Pediatr Res 94, 1308–1316 (2023). https://doi.org/10.1038/s41390-023-02625-y

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