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J Exp Med. 2019 Apr 1;216(4):936-949. doi: 10.1084/jem.20180009. Epub 2019 Mar 18.

Targeting VE-PTP phosphatase protects the kidney from diabetic injury.

Author information

1
Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL.
2
Division of Nephrology/Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL.
3
Eli Lilly & Company, Biotechnology Discovery Research, Indianapolis, IN.
4
Department of Radiology and Biomedical Engineering, Northwestern University, Feinberg School of Medicine, Chicago, IL.
5
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
6
Max Planck Institute for Molecular Biomedicine, Münster, Germany.
7
Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL quaggin@northwestern.edu.

Abstract

Diabetic nephropathy is a leading cause of end-stage kidney failure. Reduced angiopoietin-TIE2 receptor tyrosine kinase signaling in the vasculature leads to increased vascular permeability, inflammation, and endothelial cell loss and is associated with the development of diabetic complications. Here, we identified a mechanism to explain how TIE2 signaling is attenuated in diabetic animals. Expression of vascular endothelial protein tyrosine phosphatase VE-PTP (also known as PTPRB), which dephosphorylates TIE2, is robustly up-regulated in the renal microvasculature of diabetic rodents, thereby reducing TIE2 activity. Increased VE-PTP expression was dependent on hypoxia-inducible factor transcriptional activity in vivo. Genetic deletion of VE-PTP restored TIE2 activity independent of ligand availability and protected kidney structure and function in a mouse model of severe diabetic nephropathy. Mechanistically, inhibition of VE-PTP activated endothelial nitric oxide synthase and led to nuclear exclusion of the FOXO1 transcription factor, reducing expression of pro-inflammatory and pro-fibrotic gene targets. In sum, we identify inhibition of VE-PTP as a promising therapeutic target to protect the kidney from diabetic injury.

PMID:
30886059
PMCID:
PMC6446875
[Available on 2019-10-01]
DOI:
10.1084/jem.20180009

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