Abstract-Rodents studies suggest that androgens are involved in sex-specific differences in blood pressure. In humans, there is no difference in blood pressure between boys and girls, but after puberty, blood pressure increases more in men than in women. We investigated androgen-dependent regulation of the ␣-subunit of the epithelial sodium channel (␣EnaC) in human kidney and in the human renal cell line immortalized human renal proximal tubular cell line (HKC-8).We used microarray technique to analyze androgen-dependent gene regulation and performed quantitative RT-PCR for verification. Promoter constructs for human ␣ENaC were used in transfection studies to analyze the regulation by testosterone. We investigated the in vivo effect of testosterone on ␣ENaC in a rat model and used the mouse collecting duct cell line M-1 for transepithelial electrophysiological measurements. The androgen receptor (AR) was expressed in male kidney and HKC-8 cells. ␣ENaC mRNA expression increased 2-to 3-fold after treatment with testosterone in HKC-8 cells. The induction by testosterone was completely blocked by adding the AR antagonist flutamide. Analysis of the ␣ENaC promoter sequence identified a putative AR response element (ARE) located 140 nucleotides upstream from the transcription start site. HKC-8 cell transfection studies showed that testosterone directly upregulated gene expression via this ARE. In vivo, testosterone treatment of orchiectomized rats resulted in an increased renal ␣ENaC mRNA expression. In testosterone-treated mouse M-1 cells, amiloride caused a significant stronger decrease in short circuit current than in control cells. These data show that ␣ENaC expression is directly regulated by androgens in vitro and in vivo and highlight a potential mechanism explaining the reported gender differences in blood pressure. Key Words: blood pressure Ⅲ gender Ⅲ kidney Ⅲ sodium channels A ndrogens are known to play an important role in renal tubular epithelial cell growth, hypertrophy, and erythropoetin production, and may be important determinants of sex-specific differences in blood pressure. 1 In spontaneously hypertensive rats, males have higher blood pressures than females, 2 an effect that is reversed by male castration. Furthermore, increases in blood pressure were observed in castrated male and female rats after the administration of testosterone, 2,3 whereas administration of the androgen receptor (AR) antagonist flutamide attenuated hypertension. 4 These studies strongly implicate androgens in the regulation of blood pressure in the rat, but the mechanisms for this are still unknown.In humans, there is no difference in blood pressure between boys and girls, but during and after puberty, boys show higher blood pressure than age-matched girls, 5,6 and men have a higher overall mean arterial pressure than women, 7 regardless of ethnic origin. 8 The higher blood pressure and stronger progression of hypertension in men is associated with a higher risk and mortality for cardiovascular diseases than in women. 9,10 Alt...
The epithelial cells of the choroid plexus (CP) are responsible for cerebrospinal fluid (CSF) secretion into the ventricles of the brain. The balance between CSF production and drainage, in part, facilitates a normal intracranial pressure. The secretion of Na(+) and anions by the CP creates an osmotic gradient driving water into the ventricles. This is opposite to classical Na(+) transporting tissues, such as the kidney, where Na(+) and water reabsorption is mediated by 11beta-hydroxysteroid dehydrogenase type 2 that protects the mineralocorticoid receptor by abrogating active cortisol to inactive cortisone. In the human ocular ciliary epithelium, Na(+) and water secretion is dependent on a novel mediator of ciliary epithelial Na(+) transport, 11beta-HSD type 1 (11beta-HSD1), that generates intraocular cortisol. In a mechanism analogous to that of the embryologically related ocular ciliary epithelium, we propose that autocrine regulation of intracranial cortisol is dependent on 11beta-HSD1 expression in the CP epithelial cells. By conducting immunolocalisation studies on brains from New Zealand White Albino rabbits, we defined the expression of 11beta-HSD1 in the secretory CP epithelial cells. Enzyme assays performed on intact rabbit CP whole tissue explants confirmed predominant 11beta-HSD1 activity, generating cortisol that was inhibited by glycyrrhetinic acid (an 11beta-HSD inhibitor). Using the real time-polymerase chain reaction, rabbit CP tissue was found to express levels of 11beta-HSD1, glucocorticoid receptor alpha and serum and glucocorticoid-regulated kinase 1 mRNA comparable to that expressed in rabbit ocular ciliary body, thereby highlighting the similarity between these two tissues. Furthermore, an enzyme-linked immunosorbent assay of rabbit CSF revealed a median cortisol concentration of 1.7 nmol/l (range 1.4-4.3 nmol/l, n = 9). Our data have identified a functional 11beta-HSD1 within the CP, mediating intracranial cortisol bioavailability. Expression of 11beta-HSD1 may be fundamental in the regulation of CSF secretion and the local generation of cortisol may represent a pathophysiological mechanism underlying cortisol-dependent neuroendocrine diseases.
Glucocorticoids (GCs) have a profound effect on adipose biology increasing tissue mass causing central obesity. The pre-receptor regulation of GCs by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that activates cortisol from cortisone has been postulated as a fundamental mechanism underlying the metabolic syndrome mediating adipocyte hyperplasia and hypertrophy in the omental (OM) depot. Orbital adipose tissue (OF) is the site of intense inflammation and tissue remodelling in several orbital inflammatory disease states. In this study, we describe features of the GC metabolic pathways in normal human OF depot and compare it with subcutaneous (SC) and OM depots. Using an automated histological characterisation technique, OF adipocytes were found to be significantly smaller (parameters: area, maximum diameter and perimeter) than OM and SC adipocytes (P<0·001). Although immunohistochemical analyses demonstrated resident CD68+ cells in all three whole tissue adipose depots, OF CD68 mRNA and protein expression exceeded that of OM and SC (mRNA, P<0·05; protein, P<0·001). In addition, there was higher expression of glucocorticoid receptor (GR)α mRNA in the OF whole tissue depot (P<0·05). Conversely, 11β-HSD1 mRNA together with the markers of late adipocyte differentiation (FABP4 and G3PDH) were significantly lower in OF. Primary cultures of OF preadipocytes demonstrated predominant 11β-HSD1 oxo-reductase activity with minimal dehydrogenase activity. Orbital adipocytes are smaller, less differentiated, and express low levels of 11β-HSD1 but abundant GRα compared with SC and OM. OF harbours a large CD68+ population. These characteristics define an orbital microenvironment that has the potential to respond to sight-threatening orbital inflammatory disease.
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