Angiotensin II induces renal plasminogen activator inhibitor-1 and cyclooxygenase-2 expression post-transcriptionally via activation of the mRNA-stabilizing factor human-antigen R.

Abstract

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.

• Authors: Anke Doller, Stefan Gauer, Ewelina Sobkowiak, Helmut Geiger, Josef Pfeilschifter, Wolfgang Eberhardt
• Journal: The American journal of pathology (Am J Pathol) Vol. 174 Issue 4 Pg. 1252-63 (Apr 2009) ISSN: 1525-2191 [Electronic] United States
• PMID: 19246637 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Surface
• ELAV Proteins
• ELAV-Like Protein 1
• ELAVL1 protein, human
• Plasminogen Activator Inhibitor 1
• RNA, Messenger
• RNA-Binding Proteins
• Angiotensin II
• Cyclooxygenase 2

Topics

• Angiotensin II (metabolism, pharmacology)
• Animals
• Antigens, Surface (metabolism)
• Cyclooxygenase 2 (metabolism)
• ELAV Proteins
• ELAV-Like Protein 1
• Electrophoretic Mobility Shift Assay
• Fibrosis
• Fluorescent Antibody Technique
• Gene Expression Regulation
• Humans
• Hypertension (complications)
• Immunohistochemistry
• Immunoprecipitation
• Kidney Diseases (etiology, metabolism)
• Male
• Plasminogen Activator Inhibitor 1 (metabolism)
• Protein Processing, Post-Translational (physiology)
• RNA, Messenger
• RNA-Binding Proteins (metabolism)
• Rats
• Rats, Sprague-Dawley
• Reverse Transcriptase Polymerase Chain Reaction