Targeting VE-PTP phosphatase protects the kidney from diabetic injury.
J Exp Med
; 216(4): 936-949, 2019 04 01.
Article
in En
| MEDLINE
| ID: mdl-30886059
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Receptor, TIE-2
/
Diabetic Nephropathies
/
Receptor-Like Protein Tyrosine Phosphatases, Class 3
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
J Exp Med
Year:
2019
Document type:
Article
Affiliation country:
Israel