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Blockade of STAT3 signaling alleviates the progression of acute kidney injury to chronic kidney disease through antiapoptosis

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Issue Date
2022-05
Publisher
American Physiological Society
Citation
American Journal of Physiology - Renal Physiology, Vol.322 No.5, pp.F553-F572
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a pivotal mediator of IL-6-type cytokine signaling. However, the roles of its full-length and truncated isoforms in acute kidney injury (AKI) and its transition to chronic kidney disease (CKD) remain elusive. Herein, the role of STAT3 isoforms in the AKI-to-CKD transition was characterized using an ischemia-reperfusion injury (IRI) mouse model. The STAT3 inhibitor Stattic was administered to C57BL/6 mice 3 h before IRI. Intrarenal cytokine expression was quantified using real-time PCR and FACS. The effect of Stattic on human tubular epithelial cells cultured under hypoxic conditions was also evaluated. Phosphorylated (p)STAT3 isoforms were detected by Western blot analysis. Stattic treatment attenuated IRI-induced tubular damage and inflammatory cytokine/chemokine expression while decreasing macrophage infiltration and fibrosis in mouse unilateral IRI and unilateral ureteral obstruction models. Similarly, in vitro STAT3 inhibition downregulated fibrosis and apoptosis in 72-h hypoxia-induced human tubular epithelial cells and reduced pSTAT3 alpha-mediated inflammation. Moreover, pSTAT3 expression was increased in human acute tubular necrosis and CKD tissues. STAT3 activation is associated with IRI progression, and STAT3 alpha may be a significant contributor. Hence, STAT3 may affect the AKI-to-CKD transition, suggesting a novel strategy for AKI management with STAT3 inhibitors. NEW & NOTEWORTHY We found that IRI increased expression of STAT3 in murine kidneys, along with inflammation markers. Through the investigation of the role of STAT3 in the AKI-to-CKD transition mechanism using mouse unilateral IRI and unilateral ureteral obstruction models and 24- or 72-h hypoxic induction of primary cultured human tubular epithelial cells, we found that STAT3 could affect the AKI-to-CKD transition. We also observed different degrees of expression in STAT3 isoforms in these processes.
ISSN
1931-857X
URI
https://hdl.handle.net/10371/182696
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Medicine (의학과)Journal Papers (저널논문_의학과)
College of Medicine/School of Medicine (의과대학/대학원)Dept. of Medicine (의학과)Journal Papers (저널논문_의학과)
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