Diabetes-induced extracellular matrix protein expression is mediated by transcription coactivator p300.
Increased fibronectin expression is a key feature of diabetic angiopathy. We have previously shown that nuclear factor-kappaB (NF-kappaB) mediates fibronectin expression in endothelial cells and in organs affected by diabetes complications. p300, a transcription coactivator, may regulate NF-kappaB activity via poly(ADP-ribose) polymerase (PARP) activation. Hence, we examined the role of p300 in fibronectin expression in diabetes. High glucose induced fibronectin expression in the endothelial cells, which was associated with increased p300, PARP activity, and NF-kappaB activation. This p300 alteration is mediated by mitogen-activated protein kinase and protein kinase C and B. We then used p300 small interfering RNA (siRNA) and showed decreased fibronectin and PARP expression, as well as NF-kappaB activation, in the endothelial cells. Examination of the heart tissues of streptozotocin-induced diabetic mice revealed increased fibronectin and p300 mRNA. Intravenous injection of p300 siRNA resulted in decreased p300 levels and normalized fibronectin expression in the heart. We further investigated retinal tissues from streptozotocin-induced diabetic rats treated with intravitreal p300 siRNA injection. Similar to the heart, p300 siRNA inhibited fibronectin expression in the retina of the diabetic animals. These results indicate that transcriptional coactivator p300 may regulate fibronectin expression via PARP and NF-kappaB activation in diabetes.
Kaur
Harkiran
H
Department of Pathology, 4011 Dental Sciences Building, University of Western Ontario, London, Ontario, Canada.
Chen
Shali
S
Xin
Xiping
X
Chiu
Jane
J
Khan
Zia A
ZA
Chakrabarti
Subrata
S
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D003920:Diabetes Mellitus / Q000235:genetics; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005353:Fibronectins / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014471:Umbilical Veins
D017931:DNA Primers; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050881:E1A-Associated p300 Protein; D011065:Poly(ADP-ribose) Polymerases