Role of the prorenin receptor in endometrial cancer cell growth.

Endometrial cancer is the most diagnosed gynecological malignancy. Despite numerous scientific advances, the incidence and mortality rate of endometrial cancer continues to rise. Emerging evidence suggests a putative role of the (pro)renin receptor ((P)RR), in the ontogenesis of endometrial cancer. The (P)RR is implicated in breast cancer and pancreatic carcinoma pathophysiology by virtue of its role in proliferation, angiogenesis, fibrosis, migration and invasion. Thus, we aimed to investigate the functional role of the (P)RR in human endometrial cancer. We employed an siRNA-mediated knockdown approach to abrogate (P)RR expression in the endometrial epithelial cell lines; Ishikawa, AN3CA and HEC-1-A and examined cellular proliferation and viability. We also carried out a sophisticated proteomic screen to explore potential pathways via which the (P)RR is acting in endometrial cancer physiology. These data confirmed that the (P)RR is critical for endometrial cancer development, contributing to both its proliferative capacity and in the maintenance of cell viability. This is likely mediated through proteins such as MGA, SLC4A7, SLC7A11 or DHRS2, which were reduced following (P)RR knockdown. These putative protein interactions/pathways, which rely on the presence of the (P)RR, are likely to contribute to endometrial cancer progression and could therefore, represent several novel therapeutic targets for endometrial cancer.

Urinary angiotensinogen excretion in Australian Indigenous and non-Indigenous pregnant women.

The intrarenal renin-angiotensin system (iRAS) is implicated in the pathogenesis of hypertension, chronic kidney disease and diabetic nephropathy. Urinary angiotensinogen (uAGT) levels reflect the activity of the iRAS and are altered in women with preeclampsia. Since Indigenous Australians suffer high rates and early onset of renal disease, we hypothesised that Indigenous Australian pregnant women, like non-Indigenous women with pregnancy complications, would have altered uAGT levels. The excretion of RAS proteins was measured in non-Indigenous and Indigenous Australian women with uncomplicated or complicated pregnancies (preeclampsia, diabetes/gestational diabetes, proteinuria/albuminuria, hypertension, small/large for gestational age, preterm birth), and in non-pregnant non-Indigenous women. Non-Indigenous pregnant women with uncomplicated pregnancies, had higher uAGT/creatinine levels than non-Indigenous non-pregnant women (P < 0.01), and levels increased as pregnancy progressed (P < 0.001). In non-Indigenous pregnant women with pregnancy complications, uAGT/creatinine was suppressed in the third trimester (P < 0.01). In Indigenous pregnant women with uncomplicated pregnancies, there was no change in uAGT/creatinine with gestational age and uAGT/creatinine was lower in the 2nd and 3rd trimesters than in non-Indigenous pregnant women with uncomplicated pregnancies (P < 0.03, P < 0.007, respectively). The uAGT/creatinine ratios of Indigenous women with uncomplicated or complicated pregnancies were the same. A decrease in uAGT/creatinine with advancing gestational age was associated with increased urinary albumin/creatinine, as is seen in preeclampsia, but it was not specific for this disorder. The reduced uAGT/creatinine in Indigenous pregnant women may reflect subclinical renal dysfunction which limits the ability of the kidney to maintain sodium balance and could indicate an increased risk of pregnancy complications and/or future renal disease.

Distinct neuroendocrine mechanisms control neural activity underlying sex differences in sexual motivation and performance.

Sexual behavior can be usefully parsed into an appetitive and a consummatory component. Both appetitive and consummatory male-typical sexual behaviors (respectively, ASB and CSB) are activated in male Japanese quail by testosterone (T) acting in the medial preoptic nucleus (POM), but never observed in females. This sex difference is based on a demasculinization (= organizational effect) by estradiol during embryonic life for CSB, but a differential activation by T in adulthood for ASB. Males expressing rhythmic cloacal sphincter movements (RCSMs; a form of ASB) or allowed to copulate display increased Fos expression in POM. We investigated Fos brain responses in females exposed to behavioral tests after various endocrine treatments. T-treated females displayed RCSM, but never copulated when exposed to another female. Accordingly they showed an increased Fos expression in POM after ASB but not CSB tests. Females treated with the aromatase inhibitor Vorozole in ovo and T in adulthood displayed both male-typical ASB and CSB, and Fos expression in POM was increased after both types of tests. Thus, the neural circuit mediating ASB is present or can develop in both sexes, but is inactive in females unless they are exposed to exogenous T. In contrast, the neural mechanism mediating CSB is not normally present in females, but can be preserved by blocking the embryonic production of estrogens. Overall these data confirm the difference in endocrine controls and probably neural mechanisms supporting ASB and CSB in quail, and highlight the complexity of mechanisms underlying sexual differentiation of behavior.