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Kidney Week

Abstract: SU-OR06

Targeting Angiopoietin-Tie2 Signaling in Kidney Ischemia-Reperfusion Injury

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Li, Yanyang, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Onay, Tuncer, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Liu, Pan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Ryczko, Michael, Mannin Research Inc, Toronto, Ontario, Canada
  • Ansari, Mohammed Javeed, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Jin, Jing, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

The endothelial angiopoietin (ANG)–Tie2 signaling pathway is required for vascular development and homeostasis. Dysregulation of ang-Tie2 pathway has been implicated in diseases including venous malformation, glaucoma, diabetic nephropathy, and septic acute kidney injury (AKI). The endothelial-specific phosphatase VE-PTP/PTPRB is a negative regulator of Tie2 phosphorylation. Here we investigate the therapeutic roles of Angiopoietin/Tie2 signaling in kidney ischemia-reperfusion injury (IRI).

Methods

A bitransgenic doxycycline-inducible system (Veptpflox/flox, Rosa26-rtTA+/+, tetO-CreTg/+) was used to knockout VE-PTP at postnatal day 0 (VE-PTPiKO). Adult male VE-PTPiKO and littermate control mice underwent bilateral IRI or sham surgery. Serum creatinine was measured on day1, day3 and day7 after surgery by HPLC method. Data were analyzed using two-way ANOVA. Tissues were harvested on day 7 for histology, immunohistochemistry and RNA/protein analysis. Bulk RNAseq was performed with RNA extracted from whole kidney 5 hours after IRI. Normalization and differential expression were determined using DESeq2. For pharmacological studies, adult male C57BL/6J mice were used. A new soluble ANGPT1 mimetic (C4BP-ANG1) or vehicle were administered by intraperitoneal injection.

Results

Western blot analysis showed VE-PTP protein levels were increased in kidneys post-IRI and following hypoxia-inducible factor stabilization. Genetic deletion of VE-PTP rescued declined Tie2 phosphorylation in kidney after IRI. While serum Creatinine was elevated 1day post-IRI in control mice, this increase was minimal in VE-PTP iKO mice (p=0.0055). Global gene expression analysis indicated minimal kidney transcriptome change at base line whereas in the setting of IRI, VEPTPiKO mice showed a less activated renal endothelium and downregulation of acute stress response gene signature. A corresponding decrease in pro-fibrotic genes was observed in VE-PTPiKO mice on day7. In the pharmacological study, systemic administration of C4BP-ANG1 activated Tie2 and its downstream AKT/eNOS/NO pathways in mouse kidney in physiological condition. Ongoing studies are analyzing its protective effect in ischemic AKI.

Conclusion

Our data provide evidence for augmenting Tie2 activation-induced vascular protection as a promising therapeutic strategy for renal protection following IR-AKI.

Funding

  • NIDDK Support