Angiopoietin-1 inhibits mouse glomerular endothelial cell senescence via Tie2 receptor-modulated ERK1/2 signaling.
BACKGROUND
The vasculature plays a key role in the progression of renal damage in aging, with reduction in glomerular and peritubular capillary density and decreased endothelial proliferative response. In this study, we examined the role of angiopoietin-1 (Ang1) in H(2)O(2)-induced senescence in mouse glomerular endothelial cells (MGECs) and the signaling pathway involved.


METHODS
MGECs were subjected to H(2)O(2)-induced senescence, which was evaluated by senescence-associated beta-galactosidase (SA-beta-Gal) staining, cell cycle analysis and expression of p16. Endothelial cell function was assessed by nitric oxide, von Willebrand factor secretion and capillary-like structure formation. Signal transduction was examined by Western blot with or without a specific inhibitor.


RESULTS
Ang1 significantly inhibited H(2)O(2)-induced senescence in MGECs, attenuated SA-beta-Gal activity, resumed growth, and downregulated p16(INK4a) levels. Moreover, Ang1 regulated the secretion and capillary-like structure formation of endothelial cells with aging. However, these changes were markedly blocked by treatment with Ang2, sTie2-Fc and PD98059. Ang1 treatment markedly increased elevated Tie2 and ERK1/2 phosphorylation levels which were reduced by Ang2 and sTie2-Fc. PD98059 substantially reduced senescence while not altering Ang1-stimulated phosphor-Tie2 stimulation.


CONCLUSIONS
The present studies suggest that Ang1 inhibits H(2)O(2)-induced senescence in MGECs via the Ang1-Tie2-ERK1/2 signaling pathway.
Yang
Min
M
Huashan Hospital, Institute of Nephrology, Fudan University, Shanghai, China.
Zhang
Minmin
M
Chen
Jing
J
Mukherjee
Rajarshi
R
Zhang
Liyin
L
Lin
Shanyan
S
Gu
Yong
Y
D042683:Angiopoietin-1 / Q000378:metabolism*; D000818:Animals; D016922:Cellular Senescence / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism*; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D042787:Receptor, TIE-2 / Q000378:metabolism*; D015398:Signal Transduction
D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; D042787:Receptor, TIE-2; D048052:Mitogen-Activated Protein Kinase 3