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

doi:10.1084/jem.20180009

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 journal › Article › peer-review

39 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 language	English (US)
Pages (from-to)	936-949
Number of pages	14
Journal	Journal of Experimental Medicine
Volume	216
Issue number	4
DOIs	https://doi.org/10.1084/jem.20180009
State	Published - Apr 1 2019

Funding

This study was funded by National Institute of Health grants R01HL124120, T32DK108738, R01EY025799, and P30DK114857 (S.E. Quaggin). I.A. Carota was supported by the Lilly Innovation Fellowship Award program from Eli Lilly. Imaging was performed at the Northwestern University Center for Advanced Microscopy and supported by National Cancer Institute CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. The genetically engineered mice were generated with the assistance of Northwestern University Transgenic and Targeted Mutagenesis Laboratory (National Institutes of Health grant CA060553). The metabolic analysis was supported by the Comprehensive Metabolic Core at Northwestern University.

ASJC Scopus subject areas

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1084/jem.20180009

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

@article{4860610da8d54353919f55d01dcbb53a,

title = "Targeting VE-PTP phosphatase protects the kidney from diabetic injury",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2019 Carota et al.",

year = "2019",

month = apr,

day = "1",

doi = "10.1084/jem.20180009",

language = "English (US)",

volume = "216",

pages = "936--949",

journal = "Journal of Experimental Medicine",

issn = "0022-1007",

publisher = "Rockefeller University Press",

number = "4",

}

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 2019, 'Targeting VE-PTP phosphatase protects the kidney from diabetic injury', Journal of Experimental Medicine, vol. 216, no. 4, pp. 936-949. https://doi.org/10.1084/jem.20180009

TY - JOUR

T1 - Targeting VE-PTP phosphatase protects the kidney from diabetic injury

AU - Carota, Isabel A.

AU - Kenig-Kozlovsky, Yael

AU - Onay, Tuncer

AU - Scott, Rizaldy

AU - Thomson, Benjamin R.

AU - Souma, Tomokazu

AU - Bartlett, Christina S.

AU - Li, Yanyang

AU - Procissi, Daniele

AU - Ramirez, Veronica

AU - Yamaguchi, Shinji

AU - Tarjus, Antoine

AU - Tanna, Christine E.

AU - Li, Chengjin

AU - Eremina, Vera

AU - Vestweber, Dietmar

AU - Oladipupo, Sunday S.

AU - Breyer, Matthew D.

AU - Quaggin, Susan E.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85063755950&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85063755950&partnerID=8YFLogxK

U2 - 10.1084/jem.20180009

DO - 10.1084/jem.20180009

M3 - Article

C2 - 30886059

AN - SCOPUS:85063755950

SN - 0022-1007

VL - 216

SP - 936

EP - 949

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 4

ER -

Targeting VE-PTP phosphatase protects the kidney from diabetic injury

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this