scholarly journals Developmental programming: prenatal androgen excess disrupts ovarian steroid receptor balance

Reproduction ◽  
2009 ◽  
Vol 137 (5) ◽  
pp. 865-877 ◽  
Author(s):  
Hugo H Ortega ◽  
Natalia R Salvetti ◽  
Vasantha Padmanabhan
Keyword(s):  
Protein Expression ◽  
Granulosa Cells ◽  
Steroid Receptor ◽  
Developmental Trajectory ◽  
Receptor Expression ◽  
Model Systems ◽  
Receptor Protein ◽  
Androgen Excess ◽  
Ovarian Steroid ◽  
Prenatal Androgen

Steroid hormones play an important role in reproduction and the receptors through which they signal change in a developmental time, follicle stage, and cell-specific manner. Disruption in steroid receptor expression affects follicle formation and differentiation. In this study, using prenatal testosterone (T) and dihydrotestosterone (DHT)-treated female sheep as model systems, we tested the hypothesis that prenatal androgen excess disrupts the developmental ontogeny of ovarian steroid receptor protein expression. Pregnant Suffolk ewes were injected twice weekly with T propionate or DHT propionate (a non-aromatizable androgen) in cottonseed oil from days 30 to 90 of gestation. Changes in ovarian estrogen receptors (ER; ESR1, ESR2), androgen receptor (AR) and progesterone receptor (PGR) proteins were determined at fetal (days 90 and 140), postpubertal (10 months), and adult (21 months; only prenatal T-treated sheep studied) ages by immunohistochemistry. Prenatal T and DHT treatment induced selective increase in AR but not ER or PGR expression in the stroma and granulosa cells of fetal days 90 and 140 ovaries. An increase in ESR1 and decrease in ESR2 immunostaining coupled with increased AR expression were evident in granulosa cells of antral follicles of 10- and 21-month-old prenatal T but not DHT-treated females (analyzed only at 10 months). These findings provide evidence that an early increase in ovarian AR is the first step in the altered ovarian developmental trajectory of prenatal T-treated females, and manifestations of postnatal ovarian dysfunction are likely facilitated via altered equilibrium of antral follicular granulosa cell ER/AR protein expression.

Daidzein affects steroidogenesis and oestrogen receptor expression in medium ovarian follicles of pigs

2013 ◽  
Vol 61 (1) ◽  
pp. 85-98 ◽  
Author(s):  
Anna Nynca ◽  
Dominika Słonina ◽  
Olga Jablońska ◽  
Barbara Kamińska ◽  
Renata Ciereszko
Keyword(s):  
Protein Expression ◽  
Granulosa Cells ◽  
Oestrogen Receptor ◽  
Receptor Expression ◽  
Progesterone Production ◽  
Progesterone Secretion ◽  
Mrna And Protein Expression ◽  
Induced Changes ◽  
Reproductive Processes

Daidzein, a phytoestrogen present in soybean products used in swine feed, has been demonstrated to affect both reproductive and endocrine functions. The aims of this study were to examine the in vitro effects of daidzein on (1) progesterone (P4) and oestradiol (E2) secretion by porcine luteinised granulosa cells harvested from medium follicles, and (2) the mRNA and protein expression of oestrogen receptors α and β (ERα and ERβ) in these cells. The influence of E2 on P4 secretion and ERα and ERβ expression in the granulosa cells of pigs was also investigated. It was found that daidzein inhibited progesterone secretion by luteinised granulosa cells isolated from medium follicles. In contrast, E2 did not affect progesterone production by these cells. Moreover, daidzein did not alter the granulosal secretion of E2. Both daidzein and E2 decreased mRNA expression of ERα in the cells examined. The expression of ERβ mRNA was not affected by daidzein but was inhibited by E2. ERα protein was not detected while ERβ protein was found in the nuclei of the cells. Daidzein and E2 upregulated the expression of ERβ protein in the cells. In summary, the phytoestrogen daidzein directly affected the porcine ovary by inhibiting progesterone production and increasing ERβ protein expression. Daidzein-induced changes in follicular steroidogenesis and granulosal sensitivity to oestrogens may disturb reproductive processes in pigs.

scholarly journals Follicle-Stimulating Hormone Receptor Polymorphism (G−29A) Is Associated with Altered Level of Receptor Expression in Granulosa Cells

2011 ◽  
Vol 96 (9) ◽  
pp. 2805-2812 ◽  
Author(s):  
Swapna S. Desai ◽  
Swati K. Achrekar ◽  
Bhakti R. Pathak ◽  
Sadhana K. Desai ◽  
Vijay S. Mangoli ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Academic Research ◽  
In Silico Analysis ◽  
Ovarian Response ◽  
Receptor Expression ◽  
Receptor Protein ◽  
Altered Level ◽  
Vitro Fertilization ◽  
Fshr Gene

Abstract Context: Polymorphisms of the FSHR gene are associated with variable ovarian response to FSH stimulation in subjects undergoing in vitro fertilization (IVF) treatment. The type of ovarian response is correlated with the level of FSH receptor (FSHR) expression on granulosa cells. Objective: We investigated whether the polymorphism at position −29 in the promoter of the FSHR gene may contribute in altered receptor expression. Design and patients: FSHR polymorphism at position −29 was studied in 100 subjects undergoing IVF treatment. Association of this polymorphism with level of FSHR expression was retrospectively analyzed. Setting: The study was conducted at an academic research institute and private IVF clinic. Methods: The genotype at position −29 of the FSHR gene was studied in IVF subjects by PCR-restriction fragment length polymorphism. Total RNA and protein was extracted from granulosa cells. The relative FSHR mRNA expression was carried out by real-time PCR. The receptor protein expression was evaluated by Western blot and confocal microscopy. Results: The clinical and endocrinological parameters revealed that almost 72% of subjects with the AA genotype at position −29 of FSHR gene were poor ovarian responders (odds ratio 8.63, 95% confidential interval 1.84–45.79; P = 0.001). The lower cleavage intensity predicted by in silico analysis for A allele as compared with the G allele suggest the difference in the DNA-protein binding affinity. The relative expression of FSHR at mRNA and protein level was significantly reduced in subjects with AA genotype as compared with the GG genotype. Conclusion: Poor ovarian response observed in subjects with the AA genotype at position −29 of the FSHR gene is due to reduced receptor expression.

Early streptozotocin-diabetes mellitus downregulates rat kidney AT2 receptors

2001 ◽  
Vol 280 (2) ◽  
pp. F254-F265 ◽  
Author(s):  
George J. Wehbi ◽  
Joseph Zimpelmann ◽  
Robert M. Carey ◽  
David Z. Levine ◽  
Kevin D. Burns
Keyword(s):  
Diabetic Nephropathy ◽  
Protein Expression ◽  
Mrna Expression ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Receptor Expression ◽  
Receptor Protein ◽  
Ang Ii ◽  
Glomerular Injury ◽  
Early Diabetes

The interaction of ANG II with intrarenal AT1 receptors has been implicated in the progression of diabetic nephropathy, but the role of intrarenal AT2 receptors is unknown. The present studies determined the effect of early diabetes on components of the glomerular renin-angiotensin system and on expression of kidney AT2receptors. Three groups of rats were studied after 2 wk: 1) control (C), 2) streptozotocin (STZ)-induced diabetic (D), and 3) STZ-induced diabetic with insulin implant (D+I), to maintain normoglycemia. By competitive RT-PCR, early diabetes had no significant effect on glomerular mRNA expression for renin, angiotensinogen, or angiotensin-converting enzyme (ACE). In isolated glomeruli, nonglycosylated (41-kDa) AT1 receptor protein expression (AT1A and AT1B) was increased in D rats, with no change in glycosylated (53-kDa) AT1 receptor protein or in AT1 receptor mRNA. By contrast, STZ diabetes caused a significant decrease in glomerular AT2 receptor protein expression (47.0 ± 6.5% of C; P < 0.001; n = 6), with partial reversal in D+I rats. In normal rat kidney, AT2 receptor immunostaining was localized to glomerular endothelial cells and tubular epithelial cells in the cortex, interstitial, and tubular cells in the outer medulla, and inner medullary collecting duct cells. STZ diabetes caused a significant decrease in AT2 receptor immunostaining in all kidney regions, an effect partially reversed in D+I rats. In summary, early diabetes has no effect on glomerular mRNA expression for renin, angiotensinogen, or ACE. AT2 receptors are present in glomeruli and are downregulated in early diabetes, as are all kidney AT2 receptors. Our data suggest that alterations in the balance of kidney AT1 and AT2 receptor expression may contribute to ANG II-mediated glomerular injury in progressive diabetic nephropathy.

scholarly journals Immunohistochemistry for (Pro)renin Receptor in Humans

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Satoshi Morimoto ◽  
Noriko Morishima ◽  
Daisuke Watanabe ◽  
Yoichiro Kato ◽  
Noriyuki Shibata ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Protein Expression ◽  
Expression Pattern ◽  
Receptor Expression ◽  
Whole Body ◽  
Receptor Protein ◽  
Pituitary Hormone ◽  
Human Organ ◽  
Human Organs ◽  
Almost All

The (pro)renin receptor is a multifunctional protein with roles in angiotensin-II-dependent and -independent intracellular cell signaling and roles as an intracellular accessory protein for the vacuolar H+-ATPase, including hormone secretion. While (pro)renin receptor mRNA is widely expressed in various human tissues, localization of (pro)renin receptor protein expression has not yet been systemically determined. Therefore, this study localized (pro)renin receptor protein expression in human organs. Systemic immunohistochemical examination of (pro)renin receptor expression was performed in whole body organs of autopsy cases. (Pro)renin receptor immunostaining was observed in the cytoplasm of cells in almost all human organs. It was observed in thyroid follicular epithelial cells, hepatic cells, pancreatic duct epithelial cells, zona glomerulosa and zona reticularis of the cortex and medulla of the adrenal gland, proximal and distal tubules and collecting ducts of the kidney, cardiomyocytes, and skeletal muscle cells. In the brain, (pro)renin receptor staining was detected in neurons throughout all areas, especially in the medulla oblongata, paraventricular nucleus and supraoptic nucleus of the hypothalamus, cerebrum, granular layer of the hippocampus, Purkinje cell layer of the cerebellum, and the pituitary anterior and posterior lobes. In the anterior lobe of the pituitary gland, all types of anterior pituitary hormone-positive cells showed double staining with (pro)renin receptor. These data showed that (pro)renin receptor protein was expressed in almost all organs of the human body. Its expression pattern was not uniform, and cell-specific expression pattern was observed, supporting the notion that (pro)renin receptor plays numerous physiological roles in each human organ.

ROS and PDFG-β receptors are critically involved in indoxyl sulfate actions that promote vascular smooth muscle cell proliferation and migration

2009 ◽  
Vol 297 (2) ◽  
pp. C389-C396 ◽  
Author(s):  
Hidehisa Shimizu ◽  
Yuichi Hirose ◽  
Fuyuhiko Nishijima ◽  
Yoshiharu Tsubakihara ◽  
Hitoshi Miyazaki
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Nadph Oxidase ◽  
Protein Expression ◽  
Receptor Expression ◽  
Indoxyl Sulfate ◽  
Receptor Protein ◽  
Uremic Toxin ◽  
Diphenylene Iodonium ◽  
Pdgf Stimulation

Patients with chronic renal failure are at greater risk of developing atherosclerosis than healthy individuals, and recent data suggest that the putative uremic toxin indoxyl sulfate (IS) promotes the pathogenesis of atherosclerosis. The present study examined the effects of IS on vascular smooth muscle cells (VSMCs) with respect to reactive oxygen species (ROS), platelet-derived growth factor (PDGF) receptors, and mitogen-activated protein kinases (MAPKs). IS induced the migration and proliferation of VSMCs and synergistically enhanced their PDGF-induced migration as well as proliferation. The effects of PDGF were promoted after a 24-h incubation with IS despite the absence of IS during PDGF stimulation. Intracellular ROS levels were increased in the presence of IS, and PDGF-dependent ROS production was augmented by a prior 24-h incubation with IS even in the absence of IS during PDGF stimulation. These data suggest that IS increases the sensitivity of VSMCs to PDGF. IS also phosphorylated PDGF-β-receptors and upregulated PDGF-β receptor but not α-receptor protein expression in the absence of exogenous PDGF. The NADPH oxidase inhibitor diphenylene iodonium blocked IS-dependent increase in receptor expression. Administration of IS to nephrectomized rats also elevated receptor protein expression in arterial VSMCs. Inhibitors of NADPH oxidase, PDGF-β receptors, extracellular-regulated protein kinase (ERK), and p38 MAPK all inhibited IS-induced VSMCs migration and proliferation. Taken together, these findings indicate that IS induces the migration as well as proliferation of VSMCs through PDGF-β receptors and that ROS generation is critically involved in this process, which promotes the development of atherosclerosis.

scholarly journals TGF-β potentiates airway smooth muscle responsiveness to bradykinin

2005 ◽  
Vol 289 (4) ◽  
pp. L511-L520 ◽  
Author(s):  
Jenny H. Kim ◽  
Deepika Jain ◽  
Omar Tliba ◽  
Bei Yang ◽  
William F. Jester ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Protein Expression ◽  
Airway Smooth Muscle ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Bronchial Hyperresponsiveness ◽  
Calcium Mobilization ◽  
Receptor Expression ◽  
Receptor Protein ◽  
Dependent Manner

The molecular mechanisms by which bradykinin induces excessive airway obstruction in asthmatics remain unknown. Transforming growth factor (TGF)-β has been involved in regulating airway inflammation and remodeling in asthma, although it is unknown whether TGF-β can modulate bradykinin-associated bronchial hyperresponsiveness. To test whether TGF-β directly modulates airway smooth muscle (ASM) responsiveness to bradykinin, isolated murine tracheal rings were used to assess whether TGF-β alters ASM contractile responsiveness to bradykinin. Interestingly, we found TGF-β-treated murine rings (12.5 ng/ml, 18 h) exhibited increased expression of bradykinin 2 (B2) receptors and became hyperreactive to bradykinin, as shown by increases in maximal contractile responses and receptor distribution. We investigated the effect of TGF-β on bradykinin-evoked calcium signals since calcium is a key molecule regulating ASM excitation-contraction coupling. We reported that TGF-β, in a dose- (0.5–10 ng/ml) and time- (2–24 h) dependent manner, increased mRNA and protein expression of the B2 receptor in cultured human ASM cells. Maximal B2 receptor protein expression that colocalized with CD44, a marker of membrane cell surface, occurred after 18 h of TGF-β treatment and was further confirmed using fluorescence microscopy. TGF-β (2.5 ng/ml, 18 h) also increased bradykinin-induced intracellular calcium mobilization in fura-2-loaded ASM cells. TGF-β-mediated enhancement of calcium mobilization was not attenuated with indomethacin, a cyclooxygenase inhibitor. These data demonstrate for the first time that TGF-β may play a role in mediating airway hyperresponsiveness to bradykinin seen in asthmatics by enhancing ASM contractile responsiveness to bradykinin, possibly as a result of increased B2 receptor expression and signaling.

scholarly journals Investigating the NPY/AgRP/GABA to GnRH Neuron Circuit in Prenatally Androgenized PCOS-Like Mice

2020 ◽  
Vol 4 (11) ◽  
Author(s):  
Christopher J Marshall ◽  
Melanie Prescott ◽  
Rebecca E Campbell
Keyword(s):  
Polycystic Ovary ◽  
Reproductive Function ◽  
Receptor Expression ◽  
Late Gestation ◽  
Gnrh Neuron ◽  
Androgen Excess ◽  
Neuron Circuit ◽  
Gaba Neurons ◽  
Gnrh Neurons ◽  
Prenatal Androgen

Abstract Polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility, is associated with altered signaling within the hormone-sensitive neuronal network that regulates gonadotropin-releasing hormone (GnRH) neurons, leading to a pathological increase in GnRH secretion. Circuit remodeling is evident between GABAergic neurons in the arcuate nucleus (ARN) and GnRH neurons in a murine model of PCOS. One-third of ARN GABA neurons co-express neuropeptide Y (NPY), which has a known yet complex role in regulating GnRH neurons and reproductive function. Here, we investigated whether the NPY-expressing subpopulation (NPYARN) of ARN GABA neurons (GABAARN) is also affected in prenatally androgenized (PNA) PCOS-like NPYARN reporter mice [Agouti-related protein (AgRP)-Cre;τGFP]. PCOS-like mice and controls were generated by exposure to di-hydrotestosterone or vehicle (VEH) in late gestation. τGFP-expressing NPYARN neuron fiber appositions with GnRH neurons and gonadal steroid hormone receptor expression in τGFP-expressing NPYARN neurons were assessed using confocal microscopy. Although GnRH neurons received abundant close contacts from τGFP-expressing NPYARN neuron fibers, the number and density of putative inputs was not affected by prenatal androgen excess. NPYARN neurons did not co-express progesterone receptor or estrogen receptor α in either PNA or VEH mice. However, the proportion of NPYARN neurons co-expressing the androgen receptor was significantly elevated in PNA mice. Therefore, NPYARN neurons are not remodeled by prenatal androgen excess like the wider GABAARN population, indicating GABA-to-GnRH neuron circuit remodeling occurs in a presently unidentified non-NPY/AgRP population of GABAARN neurons. NPYARN neurons do, however, show independent changes in the form of elevated androgen sensitivity.

scholarly journals The effect of aging on adrenergic and nonadrenergic receptor expression and responsiveness in canine skeletal muscle

2012 ◽  
Vol 112 (5) ◽  
pp. 841-848 ◽  
Author(s):  
D. S. DeLorey ◽  
P. S. Clifford ◽  
S. Mittelstadt ◽  
M. M. Anton ◽  
H. A. Kluess ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Protein Expression ◽  
Receptor Expression ◽  
Treadmill Running ◽  
Receptor Protein ◽  
Y1 Receptor ◽  
Arterial Blood ◽  
Age Related ◽  
Feed Arteries

We tested the hypothesis that adrenergic and nonadrenergic receptor responsiveness and protein expression would be altered with advancing age. Young ( n = 6; 22 ± 1 mo; mean ± SE) and old ( n = 6; 118 ± 9 mo) beagles were instrumented with flow probes and an indwelling catheter for continuous measurement of external iliac blood flow and arterial blood pressure. Vascular conductance (VC) was calculated as hindlimb blood flow/mean arterial pressure. Selective agonists for α-1, α-2, neuropeptide-Y (NPY), and purinergic (P2X) receptors were infused at rest and during treadmill running at moderate (2.5 mph) and heavy (4 mph with 2.5% grade) exercise intensities. Feed arteries were dissected from gracilis muscles, and α-1D, α-1B, α-2A, P2X-4, P2X-1, and NPY-Y1 receptor protein expression was determined. Phenylephrine produced similar decreases ( P > 0.05) in VC in young and old beagles at rest (young: −62 ± 5%; old: −59 ± 5%) and during moderate (young: −67 ± 5%; old: −62 ± 4%) and heavy (young: −54 ± 4%; old: −49 ± 3%) exercise. Clonidine caused similar ( P > 0.05) decreases in VC in old compared with young dogs at rest (young: −59 ± 8%; old: −70 ± 6%) and during moderate (young: −52 ± 6%; old: −47 ± 5%)- and heavy (young: −42 ± 5%; old: −43 ± 5%)-intensity exercise. NPY infusion resulted in a similar decline in VC in young and old beagles at rest (young: −40 ± 7%; old: −39 ± 9%) and during moderate (young: −47 ± 6%; old: −40 ± 6%)- and heavy (young: −40 ± 3%; old: −38 ± 4%)-intensity exercise. α-β-Methylene-ATP also produced similar decreases in VC in young and old beagles at rest (young: −36 ± 6%; old: −40 ± 8%) and during exercise at moderate (young: −42 ± 5%; old: −40 ± 9%) and heavy (young: −47 ± 5%; old: −42 ± 8%) intensities. α-1B receptor protein expression was elevated ( P < 0.05) in old compared with young dogs, whereas there were no age-related differences in α-1D or α-2A receptor expression and nonadrenergic P2X-4, P2X-1, and NPY-Y1 receptor expression. The present findings indicate that postsynaptic adrenergic and nonadrenergic receptor responsiveness was not altered by advancing age. Moreover, the expression of adrenergic and nonadrenergic receptors in skeletal-muscle feed arteries was largely unaffected by aging.

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