Activation of the retinoid X receptor modulates angiotensin II-induced smooth muscle gene expression and inflammation in vascular smooth muscle cells.
Lehman AM, Montford JR, Horita H, Ostriker AC, Weiser-Evans MC, Nemenoff RA, Furgeson SB.
Mol Pharmacol. 2014 Nov;86(5):570-9. doi: 10.1124/mol.114.092163. Epub 2014 Aug 28.
Levi M, Wang X, Choudhury D.
Contrib Nephrol. 2011;170:209-16. doi: 10.1159/000325668. Epub 2011 Jun 9. Review.
Abstract In spite of excellent glucose and blood pressure control, including administration of angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers, diabetic nephropathy (DN) still develops and progresses. The development of additional protective therapeutic interventions is, therefore, a major priority. Nuclear hormone receptors regulate carbohydrate metabolism, lipid metabolism, the immune response, inflammation and development of fibrosis. The increasing prevalence of DN has led to intense investigation of the role that nuclear hormone receptors may have in slowing or preventing the progression of renal disease. Several nuclear receptor-activating ligands (agonists) have been shown to have a renal protective effect in the context of DN. This review will discuss the evidence regarding the beneficial effects of the activation of the vitamin D receptor (VDR) and the farnesoid X receptor (FXR) in preventing the progression of DN, and will describe how the discovery and development of compounds that modulate the activity of VDR and FXR may provide potential additional therapeutic approaches in the management of DN.
Copyright © 2011 S. Karger AG, Basel.
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Zhang Q, He F, Kuruba R, Gao X, Wilson A, Li J, Billiar TR, Pitt BR, Xie W, Li S.
Cardiovasc Res. 2008 Feb 1;77(3):560-9. Epub 2007 Nov 13.
Abstract AIMS:The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and plays an important role in the pathogenesis of cardiovascular diseases via regulating the metabolism and transport of cholesterol. We and others have recently shown that FXR is also expressed in the vasculature, including endothelial cells and smooth muscle cells (SMC). However, the biological significance of FXR activation in SMC is still poorly understood. In this study, we examine the effect of FXR ligands on the angiotensin system in rat aortic SMC (RASMC), as angiotensin II (Ang II) signalling contributes to various types of vascular lesions by promoting cell growth of vascular SMC. METHODS AND RESULTS: Treatment of RASMC with a FXR ligand showed no obvious effect on the expression of angiotensinogen, Ang II type 1 receptor (AT1R) or type 4 receptor (AT4R) but led to a significant increase in the expression of type 2 receptor (AT2R). FXR ligand treatment also resulted in an inhibition of Ang II-mediated extracellular signal-regulated kinase (ERK) activation and growth proliferation. Promoter reporter gene and electrophoretic mobility-shift assays suggest that FXR upregulates AT2R expression at a transcriptional level. Upregulation of AT2R appears to play a role in the FXR-mediated inhibition of ERK activation via upregulation of Rous sarcoma oncogene (Src) homology domain-containing tyrosine phosphatase 1 (SHP-1) because FXR-mediated upregulation of SHP-1 can be blocked by an AT2R antagonist and FXR-mediated ERK inactivation was significantly attenuated via treatment with either an AT2R antagonist or a SHP-1 inhibitor.
CONCLUSION: (Comment: hmmmmm)FXR in SMC may serve as a novel molecular target for modulating Ang II signalling in the vasculature.
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