Role of Sex Hormones And Their Receptors On Gastric Nrf2 And Neuronal Nitric Oxide Synthase Function In An Experimental Hyperglycemia Model [post]

2019 unpublished
Gastroparesis, a condition of abnormal gastric emptying, is most commonly observed in diabetic women. To date, the role of ovarian hormones and/or gastric hormone receptors on regulating nitrergic-mediated gastric motility remains inconclusive. Aim: The purpose of this study is to investigate whether sex hormones/their receptors can attenuate altered Nuclear factor (erythroidderived 2)-like 2 (Nrf2), neuronal Nitric Oxide Synthase (nNOS) expression and nitrergic relaxation in gastric
more » ... gastric neuromuscular tissues exposed to in-vitro hyperglycemia (HG). Methods : Gastric neuromuscular sections from adult female C57BL/6J mice were incubated in normoglycemic (NG, 5mM) or hyperglycemic (30 mM or 50 mM) conditions in the presence or absence of selective estrogen receptor (ER) agonists (ERα /PPT or ERβ: DPN); or non-selective sex hormone receptor antagonists (ER/ICI 182,780, or progesterone receptor (PR)/ RU486) for 48 hours. mRNA, protein expression and nitrergic relaxation of circular gastric neuromuscular strips were assessed. Results: Our findings in HG, compared to NG, demonstrate a significant reduction in ER, Nrf2, and nNOS expression in gastric specimens. In addition, in-vitro treatment with sex hormones and/or their agonists significantly (*p<0.05) restored Nrf2/nNOSα expression and total nitrite production. Conversely, ER, but not PR, antagonist significantly reduced Nrf2/nNOSα expression and nitrergic relaxation. Conclusions: Our data suggest that ER's can regulate nitrergic function by improving Nrf2/nNOS expression in experimental hyperglycemia. Background Gastrointestinal (GI) dysfunction occurs in as many as 20-50% of patients with diabetes mellitus (T1/T2DM) [1]. Diabetic gastroparesis is a syndrome of delayed gastric emptying (GE) in the absence of mechanical obstruction of the upper stomach, antrum body, lower pyloric sphincter, and duodenum [2] [3] [4] [5] . Gastroparesis patients often experience symptoms including severe nausea, vomiting, and abdominal pain. Emerging evidence strongly indicate that women and female rodents are likely to experience more severe disease manifestations of gastroparesis compared to males [4, 6] . Interestingly, women comprise nearly 80% of the patient population, but this predisposition remains unclear. GI dysmotility, in particular, contributes to malnutrition in diabetic patients offering poor glycemic control and oral drug bioavailability among other concerns [ 7, 8] . Although options exist,
doi:10.21203/rs.2.14913/v1 fatcat:ytfgu665wzcwxkdrji5qe7areq