Abstract
STAT3 is a transcriptional regulator that plays an important role in coordinating inflammation and immunity. In addition, there is a growing appreciation of the role STAT3 signaling plays in response to organ injury following diverse insults. Acute kidney injury (AKI) from ischemia-reperfusion injury is a common clinical entity with devastating consequences, and the recognition that endothelial alterations contribute to kidney dysfunction in this setting is of growing interest. Consequently, we used a mouse with a genetic deletion of Stat3 restricted to the endothelium to examine the role of STAT3 signaling in the pathophysiology of ischemic AKI. In a mouse model of ischemic AKI, the loss of endothelial STAT3 signaling significantly exacerbated kidney dysfunction, morphologic injury, and proximal tubular oxidative stress. The increased severity of ischemic AKI was associated with more robust endothelial-leukocyte adhesion and increased tissue accumulation of F4/80+ macrophages. Moreover, important proximal tubular adaptive mechanisms to injury were diminished in association with decreased tissue mRNA levels of the epithelial cell survival cytokine IL-22. In aggregate, these findings suggest that the endothelial STAT3 signaling plays an important role in limiting kidney dysfunction in ischemic AKI and that selective pharmacologic activation of endothelial STAT3 signaling could serve as a potential therapeutic target.
Highlights
Acute kidney injury (AKI) is a costly clinical entity associated with significant morbidity and mortality [1,2,3]
These findings suggest that targeting activation of STAT3 in the kidney microvascular endothelium during ischemic injury may serve as an important therapeutic intervention to mitigate ischemic AKI
Our findings demonstrate that loss of endothelial STAT3 signaling exacerbates injury in this rodent model of ischemic AKI
Summary
Acute kidney injury (AKI) is a costly clinical entity associated with significant morbidity and mortality [1,2,3]. Ischemiareperfusion injury (IRI) is one of the most common contributors to the development of AKI in a variety of clinical scenarios and is a primary factor promoting the onset of delayed graft function following transplantation [4,5,6]. The pathophysiology of ischemic AKI involves a complex interplay between epithelial tubular injury, inflammation, and microvascular dysfunction that culminates in a decrement of glomerular filtration rate (GFR) that is the ultimate common denominator of AKI [7]. Acute alterations in the kidney microvascular endothelium have been observed in animal models of AKI [8,9,10,11], and these alterations confer a variety of functional consequences that can contribute to diminished GFR.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
