Targeting VE-PTP phosphatase protects the kidney from diabetic injury

Isabel A. Carota, Yael Kenig-Kozlovsky, Tuncer Onay, Rizaldy Scott, Benjamin R. Thomson, Tomokazu Souma, Christina S. Bartlett, Yanyang Li, Daniele Procissi, Veronica Ramirez, Shinji Yamaguchi, Antoine Tarjus, Christine E. Tanna, Chengjin Li, Vera Eremina, Dietmar Vestweber, Sunday S. Oladipupo, Matthew D. Breyer, Susan E. Quaggin*

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)936-949
Number of pages14
JournalJournal of Experimental Medicine
Volume216
Issue number4
DOIs
StatePublished - Apr 1 2019

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Carota, I. A., Kenig-Kozlovsky, Y., Onay, T., Scott, R., Thomson, B. R., Souma, T., Bartlett, C. S., Li, Y., Procissi, D., Ramirez, V., Yamaguchi, S., Tarjus, A., Tanna, C. E., Li, C., Eremina, V., Vestweber, D., Oladipupo, S. S., Breyer, M. D., & Quaggin, S. E. (2019). Targeting VE-PTP phosphatase protects the kidney from diabetic injury. Journal of Experimental Medicine, 216(4), 936-949. https://doi.org/10.1084/jem.20180009