Role of the B1 kinin receptor in the exercise-induced maternal metabolism during pregnancy and in gestational diabetes: a translational study

Abstract

Epidemiological and experimental studies with animals suggested that the first nutritional experiences of an individual; i.e., any uterine nutritional alteration, may affect the susceptibility of the fetus to develop chronic diseases related to the Metabolic Syndrome when adult, as obesity, hypertension, cardiovascular disease and Type 2 diabetes. This process is known as metabolic imprinting of fetal programming (Waterland and Garza 1999). Baker and collaborators initially proposed that the male offspring of mothers that experienced metabolic alterations such as maternal malnutrition, obesity and diabetes were born with low weight (< 2500g) and associated this low weight at birth with a higher risk of acquiring glucose intolerance and cardiovascular diseases during adulthood (Barker et al., 1993). It has been shown that proteins such as leptin (Jansson et al., 2003), Interleukin-6 (Bowen et al., 2005) and the kallikrein-kinin system (KKS) (Valdés et al., 2011) are important for the development of the placenta and of the fetus during pregnancy. The KKS is an enzymatic cascade that results in the release of vasoactive kinin peptides. It includes kinin precursors known as kininogens metabolized by plasma and tissue kallikrein. The kinins, which interact with the B2 receptor (B2R), are further process-sed by carbopeptidases to des-Arg9-kinins with higher affinity for the B1 receptor (B1R) (Bader, 2009). A plethora of studies supports the importance of the KKS in angiogenesis and arteriogenesis and in the regulation of blood flow, which is particularly important in placental development (Bader, 2009, Valdés et al., 2011, Hillmeister et al., 2011). Accordingly, alterations in the KKS are associated with pre-eclampsia, a pregnancy-associated disorder characterized by insufficient angiogenesis (Hoegh et al., 2010). Moreover, we have shown that the KKS also plays a major role in metabolism by controlling glucose homeostasis and increasing plasma leptin levels (Araujo et al., 2006, Barros et al., 2012, Mori et al., 2008). In previous joint work, the German and Brazilian groups had analyzed offspring of mothers after physical exercise. We found that neurogenesis in the brain is reduced after exercise which may be related to an increase in corticosterone levels in the mother (Wasinski et al., 2016). We also found a decreased expression of B1R, leptin, IL-6 and PIGF (Placental Growth Factor) in the placenta (unpublished data). In order to clarify the role of the KKS in metabolic imprinting we plan to evaluate the metabolism of mice deficient in the B1R (B1KO) born from exercised mothers. We intend also to mimic the exercise in a trophoblast cell line treating the cells with cortisol. Moreover, we will evaluate the expression of KKS genes in placenta of healthy and diabetic human mothers and the stress response of primary human placental cells. (AU)