We would like to thank Tinghang et al. for their interest in our manuscript and their constructive comments. In their letter, they underline information regarding the role of extracellular histones on endothelial cytotoxicity. Indeed, they refer to the work of Karki and coworkers1 that reported data from studies in pulmonary artery endothelial cells, which were similar to the data we have obtained in a human microvascular endothelial cell line and in primary human renal glomerular endothelial cells, i.e., the ability of histones H3 and H4 to induce an inflammatory response and to increase endothelial permeability and the implication of Toll-like receptor 4.
In keeping with our in vivo results showing an increase in peritubular endothelial permeability in mice with tumor lysis syndrome and mice injected with histones,2 they report that the histone subunits H3 and H4 cause endothelial barrier disruption and a decrease in vascular endothelial (VE)-cadherin expression in pulmonary endothelial cells. Disassembly of adherence junctions compromised by the integrity of the VE-cadherin adhesion complex has been described in many pathologic conditions associated with increased endothelial permeability. However, data on pulmonary endothelial cells should be interpreted with caution in the specific context of AKI due to the high degree of heterogeneity of vascular endothelial cells in different organs. Indeed, whereas the pulmonary endothelium is a continuous vascular endothelium, fenestrated endothelial cells are seated within the glomeruli and tubuli of the kidney. In human renal glomerular cells and human dermal microvascular cells, we did not observe any change in CD144 (VE-cadherin) staining after H3 stimulation. The discrepancy with the results mentioned by Tinghang et al.1,3 may be due to dissimilar expression of VE-cadherin according to endothelial cell subtypes and/or organs.4 Beyond the role of VE-cadherin, LPS-induced disruption of other tubular tight junction proteins, including zonula occludens-1, occludin, and claudins, via a Toll-like receptor 4–dependent mechanism, has also been involved in endotoxemic-mediated AKI.5,6 This could represent yet another promising pathway of investigation to decipher the mechanisms underpinning the increase of peritubular permeability induced by extracellular histones.
Overall, the published data mentioned by Tinghang et al. add further information to our results concerning the potential role of extracellular histones in endothelial permeability that may be involved in organ failure in various pathologic conditions, including tumor lysis syndrome.
Disclosures
L. Zafrani reports receiving research funding from Jazz Pharmaceuticals. All remaining authors have nothing to disclose.
Funding
None.
Footnotes
Published online ahead of print. Publication date available at www.jasn.org.
Author Contributions
L. Zafrani wrote the original draft; and all authors reviewed and edited the manuscript.
References
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