Abstract: TH-PO351

Endothelial STAT3 Modulates Protective Mechanisms in a Mouse Model of AKI

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Dube, Shataakshi, Duke University, Durham, North Carolina, United States
  • Matam, Tejasvi, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Yen, Jessica, Jackson Memorial Health Systems, Miami, Florida, United States
  • Dagher, Pierre C., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Hato, Takashi, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Sutton, Timothy A., Indiana University School of Medicine, Indianapolis, Indiana, United States
Background

Acute kidney injury (AKI) is a common clinical entity with devastating consequences. STAT3 is a transcriptional regulator that plays an important role in coordinating inflammation and there is a growing appreciation of the role STAT3 signaling plays in the response to organ injury following diverse insults. Since it is well recognized that endothelial alterations contribute to organ dysfunction in AKI, in this study we examine the role of endothelial STAT3 in a model of ischemic AKI.

Methods

A mouse with the genetic deletion of Stat3 restricted to the endothelium (eStat3-/-) was used to examine the role of endothelial STAT3 signaling in a bilateral renal artery clamp (BAC) model of ischemic AKI.

Results

Mean serum creatinine 24 hours after BAC was significantly higher in eStat3-/- mice (3.0+0.2 mg/dL) as compared to background C57BL/6 mice (1.2+0.9 mg/dL; p<0.05). Histologic damage was also significantly greater in the eStat3-/- mice with mean tubular damage scores of 3.7+5 in the eStat3-/- mice and 2.3+0.9 in the background C57BL/6 mice (p<0.05). Proximal tubular oxidant stress as determined by intravital imaging of carboxy-DCFDA fluorescence was 25% higher in eStat3-/- mice as compared to C57BL/6 mice (p<0.05). Heme oxygenase-1 (HO-1), a critical mediator of protective adaptations in the proximal tubule exposed to oxidant stress, and the expression of IL-22, a key promoter of tubular HO-1, were both significantly decreased in eStat3-/- mice as compared to C57BL/6 mice (p<0.05). Given the contribution of inflammation to oxidant stress and tubular injury during AKI and the coordinating role the microvascular endothelium plays in these responses, we examined the impact of endothelial Stat3 deletion on microvascular leukocyte trafficking and tissue leukocyte composition in this model of AKI. Leukocyte adherence to the microvascular endothelium as measured by intravital microscopy was 2-fold greater in eStat3-/- mice as compared to C57BL/6 mice (p<0.05); however, there was no significant difference in macrophage tissue infiltration between eStat3-/- and C57BL/6 mice.

Conclusion

These findings suggest 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.

Funding

  • NIDDK Support