Angiotensin II Upregulates Toll-Like Receptor 4 on Mesangial Cells
- 1 June 2006
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American Society of Nephrology
- Vol. 17 (6), 1585-1593
- https://doi.org/10.1681/asn.2005070699
Abstract
Angiotensin II (AngII) mediates proinflammatory properties by activating NF-κB transcription factor nuclear translocation and inducing the expression of chemokines. For examination of whether AngII modulates the expression of Toll-like receptor 4 (TLR4), a key element of the innate immune system that senses LPS, mouse mesangial cells (MMC) were treated with AngII. AngII upregulated TLR4 mRNA and protein in MMC, and this effect was mediated through AngII type 1 receptors. Reporter gene experiments indicate that an activating protein-1 (AP-1) as well as an E-26 specific sequence (Ets) binding site in the TLR4 promoter are responsible for the AngII-stimulated transcriptional activity of the TLR4 gene. Preincubation of MMC with AngII enhanced LPS-induced NF-κB activation and chemokine expression. Immunohistochemical analyses revealed that double-transgenic rats that overexpressed human renin and angiotensinogen expressed higher levels of glomerular TLR4 compared with normal Sprague-Dawley rats. In vivo, infusion with AngII but not with norepinephrine into rats for 7 d also enhanced glomerular NF-κB activation after systemic application of LPS, suggesting that the effects are independent of concomitantly induced hypertension. Together, these observations suggest that AngII leads to an activation of the innate immune system by a novel mechanism involving the upregulation of TLR4. Our data contribute to a better understanding of how exogenous infections may trigger renal autoimmune processes, particularly in pathophysiologic situations with high renal AngII concentrations. Because TLR4 binds endogenous ligands (e.g., extracellular matrix components) in addition to microbial products, AngII-mediated upregulation of TLR4 also could be relevant for the development of inflammation in many noninfectious renal diseases.Keywords
This publication has 37 references indexed in Scilit:
- Infections and Autoimmunity—Good or Bad?Published by The American Association of Immunologists ,2005
- Signaling DangerJournal of the American Society of Nephrology, 2004
- Toll-Like Receptor Signaling PathwaysScience, 2003
- Toll-Like ReceptorsAnnual Review of Immunology, 2003
- Inflammation and angiotensin IIThe International Journal of Biochemistry & Cell Biology, 2003
- Roles of Toll-Like Receptors in C-C Chemokine Production by Renal Tubular Epithelial CellsPublished by The American Association of Immunologists ,2002
- Role of immunocompetent cells in nonimmune renal diseasesKidney International, 2001
- Toll-like receptor–mediated NF-κB activation: a phylogenetically conserved paradigm in innate immunityJCI Insight, 2001
- Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharideJCI Insight, 2000
- A human homologue of the Drosophila Toll protein signals activation of adaptive immunityNature, 1997