Kidney Week

Abstract: SU-OR06

Targeting Angiopoietin-Tie2 Signaling in Kidney Ischemia-Reperfusion Injury

Session Information

• AKI Mechanisms: Research Abstracts
  October 25, 2020 | Location: Simulive
  Abstract Time: 05:00 PM - 07:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Li, Yanyang, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Yanyang Li, PhD

• Onay, Tuncer, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Tuncer Onay,

• Liu, Pan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Pan Liu,

• Ryczko, Michael, Mannin Research Inc, Toronto, Ontario, Canada

Michael Ryczko,

• Ansari, Mohammed Javeed, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Mohammed Javeed Ansari,

• Jin, Jing, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Jing Jin,

• Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Susan E. Quaggin,

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 (Veptp^flox/flox, Rosa26-rtTA^+/+, tetO-Cre^Tg/+) 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