Epithelial and endothelial injury and a cascade of immune and interstitial cell activation in the kidney lead to AKI. After mild to moderate AKI, the epithelium can regenerate and restore kidney function, yet little is known about the endothelium during these repair processes. Sphingosine 1-phosphate receptor 1 (S1P1), a G protein-coupled receptor, is necessary for vascular homeostasis. Here, we used an inducible genetic approach in a mouse model of AKI, ischemia-reperfusion injury (IRI), to determine the temporal effects of endothelial S1P1 during AKI. Deletion of endothelial S1P1 before IRI exacerbated kidney injury and inflammation, and the delayed deletion of S1P1 after IRI prevented kidney recovery, resulting in chronic inflammation and progressive fibrosis. Specifically, S1P1 directly suppressed endothelial activation of leukocyte adhesion molecule expression and inflammation. Altogether, the data indicate activation of endothelial S1P1 is necessary to protect from IRI and permit recovery from AKI. Endothelial S1P1 may be a therapeutic target for the prevention of early injury as well as prevention of progressive kidney fibrosis after AKI.
Journal of the American Society of Nephrology : JASN. 2016 Mar 09 [Epub ahead of print]
Heather M Perry, Liping Huang, Hong Ye, Chong Liu, Sun-Sang J Sung, Kevin R Lynch, Diane L Rosin, Amandeep Bajwa, Mark D Okusa
Departments of Medicine, Division of Nephrology and Center for Immunity, Inflammation, and Regenerative Medicine., Departments of Medicine, Division of Nephrology and Center for Immunity, Inflammation, and Regenerative Medicine., Departments of Medicine, Division of Nephrology and Center for Immunity, Inflammation, and Regenerative Medicine., Microbiology, Immunology, and Cancer Biology, and., Departments of Medicine, Division of Nephrology and Center for Immunity, Inflammation, and Regenerative Medicine., Pharmacology, University of Virginia, Charlottesville, Virginia., Pharmacology, University of Virginia, Charlottesville, Virginia., Departments of Medicine, Division of Nephrology and Center for Immunity, Inflammation, and Regenerative Medicine, ., Departments of Medicine, Division of Nephrology and Center for Immunity, Inflammation, and Regenerative Medicine, .