Human pulmonary microvascular endothelial cells respond to DAMPs from injured renal tubular cells

Author:

DeWolf Sean E.12ORCID,Hawkes Alana A.2,Kurian Sunil M.34,Gorial Diana E.2,Hepokoski Mark L.15,Almeida Stephanie S.2ORCID,Posner Isabella R.2,McKay Dianne B.24

Affiliation:

1. Department of Pulmonary and Critical Care Medicine University of California San Diego San Diego California USA

2. Department of Immunology The Scripps Research Institute La Jolla California USA

3. Scripps Clinic Bio‐Repository & Bio‐Informatics Core, Scripps Health La Jolla California USA

4. Department of Surgery Scripps Clinic and Green Hospital La Jolla California USA

5. Department of Pulmonary and Critical Care Medicine Veterans Administration San Diego California USA

Abstract

AbstractAcute kidney injury (AKI) causes distant organ dysfunction through yet unknown mechanisms, leading to multiorgan failure and death. The lungs are one of the most common extrarenal organs affected by AKI, and combined lung and kidney injury has a mortality as high as 60%–80%. One mechanism that has been implicated in lung injury after AKI involves molecules released from injured kidney cells (DAMPs, or damage‐associated molecular patterns) that promote a noninfectious inflammatory response by binding to pattern recognition receptors (PRRs) constitutively expressed on the pulmonary endothelium. To date there are limited data investigating the role of PRRs and DAMPs in the pulmonary endothelial response to AKI. Understanding these mechanisms holds great promise for therapeutics aimed at ameliorating the devastating effects of AKI. In this study, we stimulate primary human microvascular endothelial cells with DAMPs derived from injured primary renal tubular epithelial cells (RTECs) as an ex‐vivo model of lung injury following AKI. We show that DAMPs derived from injured RTECs cause activation of Toll‐Like Receptor and NOD‐Like Receptor signaling pathways as well as increase human primary pulmonary microvascular endothelial cell (HMVEC) cytokine production, cell signaling activation, and permeability. We further show that cytokine production in HMVECs in response to DAMPs derived from RTECs is reduced by the inhibition of NOD1 and NOD2, which may have implications for future therapeutics. This paper adds to our understanding of PRR expression and function in pulmonary HMVECs and provides a foundation for future work aimed at developing therapeutic strategies to prevent lung injury following AKI.

Funder

National Heart, Lung, and Blood Institute

National Institute of Diabetes and Digestive and Kidney Diseases

Publisher

Wiley

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