Blockage of angiotensin II type 1 receptor regulates TNF-α-induced MAdCAM-1 expression via inhibition of NF-κB translocation to the nucleus and ameliorates colitis

Abstract

Mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) is an important target in the treatment of inflammatory bowel disease (IBD). Recently, treatment of IBD with an antibody to alpha4beta7-integrin, a ligand for MAdCAM-1, has been an intense focus of research. Our aim was to clarify the mechanism by which MAdCAM-1 is regulated via angiotensin II type 1 receptor (AT1R), and to verify if AT1R might be a novel target for IBD treatment. The role of AT1R in the expression of MAdCAM-1 in SVEC (a murine high endothelial venule cell) and MJC-1 (a mouse colonic endothelial cell) was examined following cytokine stimulation. We further evaluated the effect of AT1R on the pathogenesis of immune-mediated colitis using AT1R-deficient (AT1R-/-) mice and a selective AT1R blocker. AT1R blocker significantly suppressed MAdCAM-1 expression induced by TNF-alpha, but did not inhibit phosphorylation of p38 MAPK or of IkappaB that modulate MAdCAM-1 expression. However, NF-kappaB translocation into the nucleus was inhibited by these treatments. In a murine colitis model induced by dextran sulfate sodium, the degree of colitis, judged by body weight loss, histological damage, and the disease activity index, was much milder in AT1R-/- than in wild-type mice. The expression of MAdCAM-1 was also significantly lower in AT1R-/- than in wild-type mice. These results suggest that AT1R regulates the expression of MAdCAM-1 under colonic inflammatory conditions through regulation of the translocation of NF-kappaB into the nucleus. Furthermore, inhibition of AT1R ameliorates colitis in a mouse colitis model. Therefore, AT1R might be one of new therapeutic target of IBD via regulation of MAdCAM-1.

Telmisartan Attenuates Colon Inflammation, Oxidative Perturbations and Apoptosis in a Rat Model of Experimental Inflammatory Bowel Disease

“…RAS has been implicated in the pathogenesis of IBD via upregulation of Ang II AT1 receptors throughout the colon [1], [8]. Ang II is involved in several key steps of the inflammatory cascade that ultimately provoke intestinal injury and ulceration including polymorphonuclear leukocyte (PMN) infiltration, probably, via upregulation of adhesion molecules [8], [42].…”

Telmisartan attenuates the inflamed mesenteric adipose tissue in spontaneous colitis by mechanisms involving regulation of neurotensin/microRNA-155 pathway

“…In addition, the renin-angiotensin system was reported to be involved in the pathophysiology of colitis, suggesting that antagonism of the renin-angiotensin system such as angiotensin II receptor may be a potential prophylactic strategy for the treatment of human IBD [74,75]. In fact, angiotensin receptor antagonist is effective in preventing experimental colitis through the blockade of growth factor-beta1 overexpression or via regulation of mucosal vascular addressin cell adhesion molecule 1 [76][77][78][79]. Therefore, considering the fact that telmisartan has its function as an angiotensin II type 1 receptor blocker and a PPAR-g agonist, we cannot rule out the possibility that telmisartan showed its ability in attenuation colon inflammation through regulation of renin-angiotensin system.…”

miR-802 regulates human angiotensin II type 1 receptor expression in intestinal epithelial C2BBe1 cells

“…Mizushima et al (43) reported that AT 1 R regulates the expression of mucosal addressin cell adhesion molecule-1 under colonic inflammatory conditions through regulation of the translocation of NF-B into the nucleus. Furthermore, they demonstrated that inhibition of the AT 1 R ameliorated colitis in a mouse colitis model (43).…”