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.
N1 - Funding Information:
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.
Publisher Copyright:
© 2019 Carota et al.
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.
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U2 - 10.1084/jem.20180009
DO - 10.1084/jem.20180009
M3 - Article
C2 - 30886059
AN - SCOPUS:85063755950
VL - 216
SP - 936
EP - 949
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 4
ER -
