Kidney Week

Abstract: TH-PO046

Inhibition of the VE-PTP Phosphatase Protects the Kidney from Ischemia-Reperfusion Injury

Session Information

• AKI: Mechanisms - Primary Injury and Repair - I
  November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

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

Yanyang Li,

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

Tuncer Onay,

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

Mohammed Javeed Ansari,

• 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 acute kidney injury (AKI). The endothelial-specific phosphatase VE-PTP/PTPRB is a crucial negative regulator of Tie2 phosphorylation status. We have previously shown that inhibition of VE-PTP is a promising therapeutic target for diabetic kidney injury in mice, but its role in acute kidney injury has not been studied. Here we hypothesize that inhibition of VE-PTP will protect the kidney from AKI due to ischemia-reperfusion injury (IR-AKI).

Methods

A bitransgenic doxycycline-inducible system (Veptp^flox/flox, Rosa26-rtTA^+/+, tetO-Cre^Tg/+) was used to knockout the VE-PTP gene from the vasculature of mice at postnatal day 0 (VE-PTPiKO). 3 month-old male VE-PTPiKO and littermate control mice underwent bilateral renal ischemia reperfusion injury (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. Kidney and lung tissues were harvested on day 7 for histology (H&E, PAS), immunohistochemistry and RNA/protein analysis.

Results

Genetic deletion of VE-PTP robustly enhanced Tie2 phosphorylation in vasculature of lung tissue and kidney tissue in vivo. Western blot analysis showed VE-PTP protein levels were increased in kidneys post-IRI and following hypoxia-inducible factor stabilization. While serum Creatinine was elevated 1day post-IRI in control mice, this increase did not occur in VE-PTP iKO mice (p=0.0055). A corresponding increase in fibrogenic factor and FOXO1 target gene CTGF was observed in control mice compared to VE-PTPiKO mice.

Conclusion

In sum, our data identify VE-PTP as a promising therapeutic target for renal protection following IR-AKI.

Funding

• NIDDK Support