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

Mar 21, 2022American journal of physiology. Renal physiology

Blocking STAT3 signaling may slow the progression from sudden kidney injury to long-term kidney disease by preventing cell death

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Abstract

Inhibition of STAT3 with Stattic decreased inflammation and fibrosis in a mouse model of acute kidney injury (AKI).

STAT3, particularly the phosphorylated form, is associated with increased inflammation and injury in acute kidney injury.
Treatment with the STAT3 inhibitor Stattic reduced tubular damage and inflammatory responses in mouse models of kidney injury.
In human cells exposed to low oxygen conditions, STAT3 inhibition decreased markers of fibrosis and cell death.
Higher levels of phosphorylated STAT3 were observed in tissues from patients with acute tubular necrosis and chronic kidney disease.
Different isoforms of STAT3 exhibited varying expression levels during the transition from AKI to chronic kidney disease.

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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 pSTAT3α-mediated inflammation. Moreover, pSTAT3 expression was increased in human acute tubular necrosis and CKD tissues. STAT3 activation is associated with IRI progression, and STAT3α may be a significant contributor. Hence, STAT3 may affect the AKI-to-CKD transition, suggesting a novel strategy for AKI management with STAT3 inhibitors.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. NEW & NOTEWORTHY

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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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