Radiation-induced activation of TGF-beta signaling pathways in relation to vascular damage in mouse kidneys.
The purpose of this study was to investigate the long-term effects of radiation-induced alterations in TGF-beta signaling pathways with respect to the development of vascular damage in the irradiated kidney. Total RNA was isolated from mouse kidneys at 1-30 weeks after irradiation, and quantitative real-time PCR analyses were performed for TGF-beta receptors (ALK1, ALK5, endoglin), downstream mediators (Smad7, CTGF), and downstream targets (PAI-1 and Id-1). Expression of endoglin and Smad7 protein as well as nucleo-cytoplasmic distribution of phospho Smad 2/3 and phospho Smad 1/5 was analyzed by immunohistochemistry. Radiation caused a rapid and persistent increase in expression of TGF-beta receptors and mediators from 1-30 weeks after treatment. Expression of Id-1, a downstream target of endothelial cell specific receptor ALK1, was transiently increased (1-10 weeks after irradiation) but returned to control levels at later times. Expression of PAI-1, a downstream target of ALK5, increased progressively from 10-30 weeks after irradiation. These results show that radiation activated TGF-beta signaling pathways in the kidney and shifted the balance in favor of ALK5 signaling, which generally inhibits endothelial cell proliferation and migration. We hypothesize that prolonged activation of ALK5 signaling and relative suppression of ALK1 signaling may provide an explanation for the telangiectatic phenotype observed in irradiated kidneys.
Kruse
Jacqueline J C M
JJ
Division of Experimental Therapy, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Floot
Ben G J
BG
te Poele
Johannes A M
JA
Russell
Nicola S
NS
Stewart
Fiona A
FA
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D015870:Gene Expression / Q000528:radiation effects; D007150:Immunohistochemistry; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000528:radiation effects*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D017931:DNA Primers; D016212:Transforming Growth Factor beta