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

Publication ,  Journal Article
Carota, IA; Kenig-Kozlovsky, Y; Onay, T; Scott, R; Thomson, BR; Souma, T; Bartlett, CS; Li, Y; Procissi, D; Ramirez, V; Yamaguchi, S; Li, C ...
Published in: J Exp Med
April 1, 2019

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.

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Published In

J Exp Med

DOI

EISSN

1540-9538

Publication Date

April 1, 2019

Volume

216

Issue

4

Start / End Page

936 / 949

Location

United States

Related Subject Headings

  • Receptor-Like Protein Tyrosine Phosphatases, Class 3
  • Receptor, TIE-2
  • RNA, Small Interfering
  • Nitric Oxide Synthase
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Kidney
  • Immunology
  • Humans
 

Citation

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Carota, I. A., Kenig-Kozlovsky, Y., Onay, T., Scott, R., Thomson, B. R., Souma, T., … Quaggin, S. E. (2019). Targeting VE-PTP phosphatase protects the kidney from diabetic injury. J Exp Med, 216(4), 936–949. https://doi.org/10.1084/jem.20180009
Carota, Isabel A., Yael Kenig-Kozlovsky, Tuncer Onay, Rizaldy Scott, Benjamin R. Thomson, Tomokazu Souma, Christina S. Bartlett, et al. “Targeting VE-PTP phosphatase protects the kidney from diabetic injury.J Exp Med 216, no. 4 (April 1, 2019): 936–49. https://doi.org/10.1084/jem.20180009.
Carota IA, Kenig-Kozlovsky Y, Onay T, Scott R, Thomson BR, Souma T, et al. Targeting VE-PTP phosphatase protects the kidney from diabetic injury. J Exp Med. 2019 Apr 1;216(4):936–49.
Carota, Isabel A., et al. “Targeting VE-PTP phosphatase protects the kidney from diabetic injury.J Exp Med, vol. 216, no. 4, Apr. 2019, pp. 936–49. Pubmed, doi:10.1084/jem.20180009.
Carota IA, Kenig-Kozlovsky Y, Onay T, Scott R, Thomson BR, Souma T, Bartlett CS, Li Y, Procissi D, Ramirez V, Yamaguchi S, Tarjus A, Tanna CE, Li C, Eremina V, Vestweber D, Oladipupo SS, Breyer MD, Quaggin SE. Targeting VE-PTP phosphatase protects the kidney from diabetic injury. J Exp Med. 2019 Apr 1;216(4):936–949.

Published In

J Exp Med

DOI

EISSN

1540-9538

Publication Date

April 1, 2019

Volume

216

Issue

4

Start / End Page

936 / 949

Location

United States

Related Subject Headings

  • Receptor-Like Protein Tyrosine Phosphatases, Class 3
  • Receptor, TIE-2
  • RNA, Small Interfering
  • Nitric Oxide Synthase
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Kidney
  • Immunology
  • Humans