Role of sex hormones and their receptors on gastric Nrf2 and neuronal nitric oxide synthase function in an experimental hyperglycemia model

Abstract

Background 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 (erythroid-derived 2)-like 2 (Nrf2), neuronal Nitric Oxide Synthase (nNOS) expression and nitrergic relaxation in gastric neuromuscular tissues exposed to in-vitro hyperglycemia (HG). Methods Gastric neuromuscular sections from adult female C57BL/6 J mice were incubated in normoglycemic (NG, 5 mM) 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 h. 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.

17β-Estradiol Suppresses Gastric Inflammatory and Apoptotic Stress Responses and Restores nNOS-Mediated Gastric Emptying in Streptozotocin (STZ)-Induced Diabetic Female Mice

“…NO is the primary neurotransmitter fueling muscle relaxation in the gut. Low-frequency EFS (2 Hz) in an organ bath elicits inhibitory relaxation in the gastric antral neuro-musculature [ 35 ]. NANC inhibitory relaxation was severely impaired in STZ-induced diabetic mice, consistent with delayed solid GE.…”

“…NO-mediated gastric relaxation was measured as reported previously [ 35 ]. Circular muscle sections of the gastric antrum were suspended between L-shaped tissue hooks in 5 mL organ baths containing Krebs buffer (pH 7.4) at 37 °C and continuously bubbled with 95% O 2 , 5% CO 2 (DMT-USA, Inc., Ann Arbor, MI, USA).…”

Insights into the Molecular Mechanisms of NRF2 in Kidney Injury and Diseases

“…First, there is heterogeneity in the expression of NRF2 and HO-1, which can vary depending on the tissue type and disease state, making the interpretation of their significance challenging [ 202 , 203 ]. Second, NRF2 and HO-1 are not specific to a particular disease or condition, and their expression can be influenced by factors other than oxidative stress or inflammation [ 204 , 205 ]. Third, age and gender can influence the sensitivity of NRF2 and HO-1 as biomarkers.…”