Angiotensin II induces renal plasminogen activator inhibitor-1 and cyclooxygenase-2 expression post-transcriptionally via activation of the mRNA-stabilizing factor human-antigen R.
Angiotensin (Ang) II-induced fibrosis of the kidney is characterized by the enhanced expression of profibrotic and proinflammatory genes, including the serine protease inhibitor plasminogen activator inhibitor-1 (PAI-1) and cyclooxygenase-2 (COX-2). In addition to transcriptional regulation, both genes are subject to post-transcriptional control by AU-rich destabilizing elements that reside within the ... 3' untranslated region of the mRNA. We demonstrated that the continuous infusion of AngII in rats induced fibrosis concomitant with a significant increase in glomerular PAI-1 and COX-2 expression levels. Using RNA pull-down assays and electromobility shift assays, we demonstrated the increased binding of the ubiquitous RNA-binding protein human-antigen R (HuR) to the mRNAs of both PAI-1 and COX-2 in the cytoplasmic fractions of renal homogenates from AngII-treated rats. Actinomycin D experiments in rat mesangial cells revealed that AngII stabilizes both mRNAs via HuR as proven by small interfering RNA. Mechanistically, AngII promotes an increase in nucleo-cytoplasmic HuR shuttling, which was blocked by the PKC inhibitor rottlerin and the type-I AngII (AT(1)) receptor antagonist valsartan but was unaffected by both AT(2) receptor antagonists PD123319 and CGP42112. Co-immunoprecipitation revealed that AngII treatment caused an increase in nuclear PKC-delta concomitant with binding to nuclear HuR both in vitro and in vivo. The post-transcriptional regulation of PAI-1 and COX-2 by PKC-delta-dependent HuR shuttling may contribute to the pathogenesis of hypertensive nephrosclerosis triggered by AngII.
Mesh Terms:
Angiotensin II, Animals, Antigens, Surface, Cyclooxygenase 2, Electrophoretic Mobility Shift Assay, Fibrosis, Fluorescent Antibody Technique, Gene Expression Regulation, Humans, Hypertension, Immunohistochemistry, Immunoprecipitation, Kidney Diseases, Male, Plasminogen Activator Inhibitor 1, Protein Processing, Post-Translational, RNA, Messenger, RNA-Binding Proteins, Rats, Rats, Sprague-Dawley, Reverse Transcriptase Polymerase Chain Reaction
Angiotensin II, Animals, Antigens, Surface, Cyclooxygenase 2, Electrophoretic Mobility Shift Assay, Fibrosis, Fluorescent Antibody Technique, Gene Expression Regulation, Humans, Hypertension, Immunohistochemistry, Immunoprecipitation, Kidney Diseases, Male, Plasminogen Activator Inhibitor 1, Protein Processing, Post-Translational, RNA, Messenger, RNA-Binding Proteins, Rats, Rats, Sprague-Dawley, Reverse Transcriptase Polymerase Chain Reaction
Am. J. Pathol.
Date: Apr. 01, 2009
PubMed ID: 19246637
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