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Therapeutic translation in acute kidney injury: the epithelial/endothelial axis
Bruce A. Molitoris
Bruce A. Molitoris
Published June 2, 2014
Citation Information: J Clin Invest. 2014;124(6):2355-2363. https://doi.org/10.1172/JCI72269.
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Review Series

Therapeutic translation in acute kidney injury: the epithelial/endothelial axis

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Abstract

Acute kidney injury (AKI) remains a major clinical event with rising incidence, severity, and cost; it now has a morbidity and mortality exceeding acute myocardial infarction. There is also a documented conversion to and acceleration of chronic kidney disease to end-stage renal disease. The multifactorial nature of AKI etiologies and pathophysiology and the lack of diagnostic techniques have hindered translation of preclinical success. An evolving understanding of epithelial, endothelial, and inflammatory cell interactions and individualization of care will result in the eventual development of effective therapeutic strategies. This review focuses on epithelial and endothelial injury mediators, interactions, and targets for therapy.

Authors

Bruce A. Molitoris

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Figure 2

Alterations in the epithelial/endothelial axis during AKI.

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Alterations in the epithelial/endothelial axis during AKI.
(A) Human kid...
(A) Human kidney biopsy with ischemic AKI (cortical area). Note the expanded interstitium, microvascular plugging, dilated tubules, and patchy nature of injury. (B) Under physiologic conditions, coordinated communication and cell-cell interactions maintains homeostasis with normal kidney function. Epithelial injury leads to apoptotic and necrotic cell death that is accompanied by cytokine, chemokine, and ROS release. These factors initiate the release of exogenous and endogenous DAMPS by resident cells, leading to activation and further injury. These signals also initiate the infiltration of professional inflammatory cells such as PMNs and monocytes, leading to enhanced inflammation and further cell injury and destruction. Inflammatory signals produce alterations in the endothelium, resulting in loss of cell-cell contact and breakdown of the ECM. Additionally, there is marked microvascular plugging mediated by adherent wbcs and rouleaux formation, leading to reduced flow and worsening ischemia. Subsequently, there is migration of some of these cells into the interstitium. Pericytes dissociate from underlying ECs and convert into myofibroblasts, which lay down collagen to initiate the fibrotic cycle.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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