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J Pharmacol Exp Ther. 2018 Oct 9. pii: jpet.118.251371. doi: 10.1124/jpet.118.251371. [Epub ahead of print]

Glucocorticoid-Induced Leucine Zipper Promotes Neutrophil and T Cell Polarization with Protective Effects in Acute Kidney Injury.

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Augusta University.
Universita degli Studi di Perugia, Italy.
Augusta University;


The glucocorticoid-induced leucine zipper (GILZ) mediates anti-inflammatory effects of glucocorticoids. Acute kidney injury (AKI) mobilizes immune/inflammatory mechanisms, causing tissue injury, but GILZ's impact in AKI is not known. Neutrophils play context-specific pro- (N1) and anti-inflammatory (N2) functional roles. Also, regulatory T lymphocytes (Tregs) and regulatory T-17 (Treg17) cells exert counter-inflammatory effects including suppression of effector T lymphocytes, e.g., Th-17 cells. Thus, utilizing cell preparations of mice kidneys subjected to AKI or sham operation, we determined the effects of GILZ on T cells and neutrophil subtypes in the context of its renoprotective effect; these studies utilized the trans activator of transcription (TAT)-GILZ or the TAT peptide. AKI increased N1 and Th-17 cells but reduced N2, Tregs and Treg17 cells in association with increased interleukin (IL)-17+ but reduced IL-10+ cells accompanied with disruption of mitochondrial membrane potential (ψm) and increased apoptosis/necrosis compared to sham kidneys. TAT-GILZ, compared to TAT, treatment reduced N1 and Th-17 cells but increased N2 and Tregs, without affecting Treg17 cells, in association with reduction in IL-17+ but increased IL-10+ cells; TAT-GILZ caused less disruption of ψm and reduced cell death in AKI. Importantly, TAT-GILZ increased perfusion of the ischemic-reperfused kidney but reduced tissue edema compared to TAT. Utilizing splenic T cells and bone marrow-derived neutrophils, we further showed marked reduction in proliferation of Th cells in response to TAT-GILZ than TAT. Collectively, the results indicate that GILZ exerts renoprotection accompanied with upregulation of regulatory/suppressive arm of immunity in AKI likely via regulating crosstalk between T cells and neutrophils.


glucocorticoids; inflammation; ischemia / reperfusion injury; kidney; lymphocytes; neutrophils

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