Estrogen prevents intestinal inflammation after trauma-hemorrhage via downregulation of angiotensin II and angiotensin II subtype I receptor

Abstract

Although angiotensin II (Ang II) plays a key role in development of organ ischemia-reperfusion injury, it remains unclear whether it is involved in development of intestinal injury following trauma-hemorrhage (T-H). Studies have shown that 17β-estradiol (E2) administration following T-H improves small intestinal blood flow; however, it is unclear whether Ang II plays a role in this E2-mediated salutary effect. Male Sprague-Dawley rats underwent laparotomy and hemorrhagic shock (removal of 60% total blood volume, fluid resuscitation after 90 min). At onset of resuscitation, rats were treated with vehicle, E2, or E2 and estrogen receptor antagonist ICI 182,780 (ICI). A separate group of rats was treated with Ang II subtype I receptor (AT1R) antagonist losartan. At 24 h after T-H, plasma Ang II, IL-6, TNF-α, intercellular adhesion molecule (ICAM)-1, cytokine-induced neutrophil chemoattractant (CINC)-1 and CINC-3 levels, myeloperoxidase (MPO) activity, and AT1R expression were determined. T-H significantly increased plasma and intestinal Ang II, IL-6, TNF-α levels, intestinal ICAM-1, CINC-1, CINC-3 levels, MPO activity, and AT1R protein compared with shams. E2 treatment following T-H attenuated increased intestinal MPO activity, Ang II level, and AT1R protein expression. ICI administration abolished the salutary effects of E2. In contrast, losartan administration attenuated increased MPO activity without affecting Ang II and AT1R levels. Thus Ang II plays a role in producing small intestine inflammation following T-H, and the salutary effects of E2 on intestinal inflammation are mediated in part by Ang II and AT1R downregulation.

Aging-related dysregulation in enteric dopamine and angiotensin system interactions: implications for gastrointestinal dysfunction in the elderly

“…It is known that the GI RAS plays important roles in a variety of intestinal processes, including absorption and secretion, motility and inflammation [ 27 , 28 , 30 ]. The local GI RAS has also been related to GI diseases such as inflammatory disorders [ 34 , 35 ], GI motility disorders, mesenteric ischemia and GI cancer [ 27 - 30 ]. The present results are also consistent with a number of studies in different tissues showing that overactivation of local or tissue RAS, via AT1 receptors and NADPH oxidase activation, mediates oxidative stress and several key events in inflammatory processes that play a major role in several aging-related diseases [ 36 , 37 ].…”

Renin angiotensin system and gender differences in dopaminergic degeneration

“…Furthermore, it has been shown that expression of vascular and renal AT1 receptors, as well as the balance between AT1 and AT2 receptors may be modulated by sex hormones, and a major role for RAS in the gender differences in the development of chronic renal and cardiovascular diseases has been proposed [ 10 - 12 ]. Several studies have revealed that estrogen-mediated down-regulation of the renin-angiotensin system (RAS) mediates beneficial effects of estrogen (E2) in several tissues [ 16 - 18 ]. Furthermore, there is substantial evidence that androgens may upregulate RAS activity and therefore amplify gender-related differences [ 10 , 19 , 20 ].…”

Brain renin-angiotensin system and dopaminergic cell vulnerability

“…However, some reported effects of estrogen replacement therapy are controversial (Shulman, 2002 ; Popat et al, 2005 ), and the age and duration of lack of estrogen in women receiving the treatment appear to be major factors in the discrepancies. Interestingly, estrogen-induced regulation of the RAS mediates beneficial effects of estrogen in several tissues (Nickenig et al, 1998 ; Dean et al, 2005 ; Chen et al, 2008 ), and interactions between estrogen and AII receptors have also been observed (Liu et al, 2002 ; Tsuda et al, 2005 ; Xue et al, 2007 ; Hoshi-Fukushima et al, 2008 ). In several recent studies we have observed that the lack of estrogen increases RAS activity in the substantia nigra in females (Rodriguez-Perez et al, 2010 , 2011 , 2012 ).…”