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Y. L. Zhang, Z. X. Zhou, Y. D. Zhang, and M. G. Parker


Prostatic steroid-binding protein (PSBP) mRNAs transcribed from the three genes C1, C2 and C3 were quantitated in neonatal rat ventral prostate by Northern blot analysis. Transcription was initiated at day 14 for C1 and C2 and day 10 for C3, and reached mature levels by day 21 for C1 and C2 and day 28 for C3. The changes of both cytoplasmic and nuclear prostatic androgen receptors in 10- to 150-day-old rats were investigated by radioligand assay and showed a fivefold transient increase between days 10 and 28. Thus there was a good correlation between the onset of PSBP gene expression and the transient increase in androgen receptors; increases in receptor concentration may be a prerequisite for changes in gene expression.

J. Endocr. (1988) 117, 361–366

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L. Zhang, J. J. Dreifuss, M. Dubois-Dauphin, and E. Tribollet


The discovery that oxytocin is synthesized and stored in corpora lutea of ruminants has fostered a renewed interest in the possible roles of oxytocin in ovarian function. In the present study we describe the distribution of binding sites for oxytocin in the guinea-pig ovary. Sections were reacted with a radioiodinated oxytocin antagonist (125I-labelled OTA) to yield autoradiograms on film. Specific binding sites for oxytocin were defined as those which bound 0·05 nmol 125I-labelled OTA/l and where 1 μmol non-radioactive oxytocin/1 displaced the radioactivity. 125I-Labelled OTA consistently labelled the ovarian stroma and the theca interna, but not the corpora lutea, the granulosa cells or the theca externa. The amount of 125I-labelled OTA bound to ovarian stroma and theca interna was high in animals killed during dioestrus, and low during and shortly after oestrus. These data suggest that the binding sites are regulated by steroid hormone levels and that in the guinea-pig ovary oxytocin could exert a role in follicular steroidogenesis, maturation or ovulation rather than in luteal function. Oxytocin-binding sites were also shown in the uterus but their numbers varied only slightly during the cycle.

Journal of Endocrinology (1991) 131, 421–426

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A Rannikko, T-L Penttilä, F-P Zhang, J Toppari, M Parvinen, and I Huhtaniemi


Stage-specific expression of the FSH receptor (FSHR) gene in the rat seminiferous epithelium was studied. Using transillumination-assisted microdissection for sample preparation and Northern hybridization for analysis of total RNA, we first reassessed the stage specificity of the FSHR gene expression in the adult rat testis. Sixfold higher FSHR mRNA levels were found in stages XIII–I compared with stage VI of the seminiferous epithelial cycle, which had the lowest signal level (P<0·01). The other stages had intermediate signal levels. In situ hybridization showed distribution of grains which confirmed the data obtained by Northern analysis. Prepubertal stage-specific FSHR gene expression was studied using in situ hybridization. Stage specificity could first be demonstrated at the age of 16 days when the average grain counts in stages I–IV were threefold higher than in stages VI–VII (P<0·01). The present data are in agreement with earlier findings on stage-specific FSH binding and FSHR gene expression using both microdissected and stage-synchronized seminiferous tubules. The onset of stage-specific FSHR gene expression is concomitant with maturation of the Sertoli cell population and completion of the first generation of spermatocytes. This supports the hypothesis that spermatogonia and spermatocytes may be involved in the regulation of FSHR gene expression.

Journal of Endocrinology (1996) 151, 29–35

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R Morishita, GH Gibbons, Y Kaneda, L Zhang, T Ogihara, and VJ Dzau

Atherosclerotic cardiovascular disease results from complex interactions among multiple genetic and environmental factors. Thus, it is important to elucidate the influence of each factor on cholesterol metabolism. For this purpose, transgenic/gene-targeting technology is a powerful tool for studying gene functions. However, this technology has several disadvantages such as being time consuming and expensive. Accordingly, we established new animal models using in vivo gene transfer technology. In this study, we examined the feasibility of the creation of a new animal model for the study of atherosclerosis. We hypothesized that apolipoprotein (apo) E-deficient mice can be created by systemic administration of antisense apo E oligodeoxynucleotides (ODN) coupled to the HVJ-liposome complex. Initially, we examined the localization and cellular fate of FITC-labeled antisense ODN administered intravenously. FITC-labeled ODN transfection by the HVJ-liposome method resulted in fluorescence in the liver, spleen and kidney, but not in other organs such as brain. Moreover, fluorescence with the HVJ-liposome method was sustained for up to 2 weeks after transfection, which resulted in a striking difference from transfection of ODN alone or ODN in liposomes without HVJ, which showed rapid disappearance of fluorescence (within 1 day). Given these unique characteristics of the HVJ-liposome method, we next examined transfection of antisense apo E ODN by intravenous administration. Transfection of antisense apo E ODN resulted in a marked reduction of apo E mRNA levels in the liver, but no change in apo B and beta-actin mRNA levels. In mice fed a normal diet, a transient increase in cholesterol and triglyceride levels was observed in the antisense apo E-treated group, but they returned to normal levels by 6 days after transfection. Similar findings were also found in mice fed a high cholesterol diet. Neither scrambled nor mismatched ODN resulted in any increase in cholesterol. To make chronic hypercholesterolemic mice, we therefore performed repeated injections of apo E antisense ODN. Whenever antisense apo E ODN were injected, mice showed a transient increase in cholesterol and triglyceride. Cumulative administration of antisense apo E ODN resulted in a sustained increase in cholesterol for up to 3 weeks after the last transfection. Finally, mice treated with repeated injections of antisense apo E every week developed sustained hypercholesterolemia and hypertriglyceridemia until withdrawal of injections. Apolipoprotein-deficient mice created by intravenous administration of antisense ODN are a promising new animal model to help understand the role of apolipoprotein in vivo and develop a new drug therapy targeting apolipoprotein.

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F Dong, X Zhang, X Yang, L B Esberg, H Yang, Z Zhang, B Culver, and J Ren

The level of the obese gene product leptin is often positively correlated with body weight, supporting the notion that hyperleptinemia contributes to obesity-associated cardiac dysfunction. However, a link between leptin levels and cardiac function has not been elucidated. This study was designed to examine the role of leptin deficiency (resulting from a point mutation of the leptin gene) in cardiomyocyte contractile function. Mechanical properties and intracellular Ca2 + transients were evaluated in ventricular myocytes from lean control and leptin-deficient ob/ob obese mice at 12 weeks of age. Cardiac ultrastructure was evaluated using transmission electron microscopy. ob/ob mice were overtly obese, hyperinsulinemic, hypertriglycemic, hypoleptinemic and euglycemic. Ultrastructural examination revealed swelling and disorganization of cristae in mitochondria from ob/ob mouse ventricular tissues. Cardiomyocytes from ob/ob mice displayed reduced expression of the leptin receptor Ob-R, larger cross-sectional area, decreased peak shortening and maximal velocity of shortening/relengthening, and prolonged relengthening but not shortening duration compared with lean counterparts. Consistent with mechanical characteristics, myocytes from ob/ob mice displayed reduced intracellular Ca2 + release upon electrical stimulus associated with a slowed intracellular Ca2 + decay rate. Interestingly, the contractile aberrations seen in ob/ob myocytes were significantly improved by in vitro leptin incubation. Contractile dysfunction was not seen in age- and gender-matched high fat-induced obese mice. These results suggested that leptin deficiency contributes to cardiac contractile dysfunction characterized by both systolic and diastolic dysfunction, impaired intracellular Ca2 + hemostasis and ultrastructural derangement in ventricular myocytes.

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Zhang S-L, X Chen, TJ Hsieh, M Leclerc, N Henley, A Allidina, JP Halle, MG Brunette, JG Filep, SS Tang, Ingelfinger JR, and JS Chan

Clinical and animal studies have shown that treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor antagonists slows the progression of nephropathy in diabetes, indicating that Ang II plays an important role in its development. We have reported previously that insulin inhibits the stimulatory effect of high glucose levels on angiotensinogen (ANG) gene expression in rat immortalized renal proximal tubular cells (IRPTCs) via the mitogen-activated protein kinase (p44/42 MAPK) signal transduction pathway. We hypothesize that the suppressive action of insulin on ANG gene expression might be attenuated in renal proximal tubular cells (RPTCs) of rats with established diabetes. Two groups of male adult Wistar rats were studied: controls and streptozotocin (STZ)-induced diabetic rats at 2, 4, 8 and 12 weeks post-STZ administration. Kidney proximal tubules were isolated and cultured in either normal glucose (i.e. 5 mM) or high glucose (i.e. 25 mM) medium to determine the inhibitory effect of insulin on ANG gene expression. Immunoreactive rat ANG (IR-rANG) in culture media and cellular ANG mRNA were measured by a specific radioimmunoassay and reverse transcription-polymerase chain reaction assay respectively. Activation of the p44/42 MAPK signal transduction pathway in rat RPTCs was evaluated by p44/42 MAPK phosphorylation employing a PhosphoPlus p44/42 MAPK antibody kit. Insulin (10(-7) M) inhibited the stimulatory effect of high glucose levels on IR-rANG secretion and ANG gene expression and increased p44/42 MAPK phosphorylation in normal rat RPTCs. In contrast, it failed to affect these parameters in diabetic rat RPTCs. In conclusion, our studies demonstrate that hyperglycaemia induces insulin resistance on ANG gene expression in diabetic rat RPTCs by altering the MAPK signal transduction pathway.

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B T Layden, V Durai, M V Newman, A M Marinelarena, C W Ahn, G Feng, S Lin, X Zhang, D B Kaufman, N Jafari, G L Sørensen, and W L Lowe Jr

Pancreatic β cells adapt to pregnancy-induced insulin resistance by unclear mechanisms. This study sought to identify genes involved in β cell adaptation during pregnancy. To examine changes in global RNA expression during pregnancy, murine islets were isolated at a time point of increased β cell proliferation (E13.5), and RNA levels were determined by two different assays (global gene expression array and G-protein-coupled receptor (GPCR) array). Follow-up studies confirmed the findings for select genes. Differential expression of 110 genes was identified and follow-up studies confirmed the changes in select genes at both the RNA and protein level. Surfactant protein D (SP-D) mRNA and protein levels exhibited large increases, which were confirmed in murine islets. Cytokine-induced expression of SP-D in islets was also demonstrated, suggesting a possible role as an anti-inflammatory molecule. Complementing these studies, an expression array was performed to define pregnancy-induced changes in expression of GPCRs that are known to impact islet cell function and proliferation. This assay, the results of which were confirmed using real-time reverse transcription-PCR assays, demonstrated that free fatty acid receptor 2 and cholecystokinin receptor A mRNA levels were increased at E13.5. This study has identified multiple novel targets that may be important for the adaptation of islets to pregnancy.

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M Tena-Sempere, PR Manna, FP Zhang, L Pinilla, LC Gonzalez, C Dieguez, I Huhtaniemi, and E Aguilar

Leptin, the product of the ob gene, is a pivotal signal in the regulation of neuroendocrine function and fertility. Although much of the action of leptin in the control of the reproductive axis is exerted at the hypothalamic level, some direct effects of leptin on male and female gonads have also been reported. Indeed, recent evidence demonstrated that leptin is able to inhibit testosterone secretion at the testicular level. However, the molecular mechanisms behind this effect remain unclear. The focus of this study was twofold: (1) to identify potential targets for leptin-induced inhibition of steroidogenesis, and (2) to characterize in detail the pattern of expression and cellular distribution of leptin receptor (Ob-R) mRNA in adult rat testis. In pursuit of the first goal, slices of testicular tissue from adult rats were incubated with increasing concentrations of recombinant leptin (10(-9)--10(-7 )M) in the presence of human chorionic gonadotropin (hCG; 10 IU/ml). In this setting, testosterone secretion in vitro was monitored, and expression levels of mRNAs encoding steroidogenic factor 1 (SF-1), steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage enzyme (P450 scc) and 17 beta-hydroxysteroid dehydrogenase type III (17 beta-HSD) were assessed by Northern hybridization. In pursuit of the second goal, the pattern of cellular expression of the Ob-R gene in adult rat testis was evaluated by in situ hybridization using a riboprobe complementary to all Ob-R isoforms. In addition, testicular expression levels of the different Ob-R isoforms, previously identified in the hypothalamus, were analyzed by means of semi-quantitative RT-PCR. In keeping with our previous data, recombinant leptin significantly inhibited hCG-stimulated testosterone secretion. In this context, leptin, in a dose-dependent manner, was able to co-ordinately decrease the hCG-stimulated expression levels of SF-1, StAR and P450 scc mRNAs, but it did not affect those of 17 beta-HSD type III. In situ hybridization analysis showed a scattered pattern of cellular expression of the Ob-R gene within the adult rat testis, including Leydig and Sertoli cells. In addition, assessment of the pattern of expression of Ob-R subtypes revealed that the long Ob-Rb isoform was abundantly expressed in adult rat testis. However, variable levels of expression of Ob-Ra, Ob-Re, and Ob-Rf mRNAs were also detected, whereas those of the Ob-Rc variant were nearly negligible. In conclusion, our results indicate that decreased expression of mRNAs encoding several up-stream elements in the steroidogenic pathway may contribute, at least partially, to leptin-induced inhibition of testicular steroidogenesis. In addition, our data on the pattern of testicular expression of Ob-R isoforms and cellular distribution of Ob-R mRNA may help to further elucidate the molecular mechanisms of leptin action in rat testis.

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Kimberley C W Wang, Kimberley J Botting, Song Zhang, I Caroline McMillen, Doug A Brooks, and Janna L Morrison

Intrauterine insults, such as poor nutrition and placental insufficiency, can alter cardiomyocyte development, and this can have significant long-term implications for heart health. Consequently, epidemiological studies have shown that low-birth-weight babies have an increased risk of death from cardiovascular disease in adult life. In addition, intrauterine growth restriction can result in increased left ventricular hypertrophy, which is the strongest predictor for poor health outcomes in cardiac patients. The mechanisms responsible for these associations are not clear, but a suboptimal intrauterine environment can program alternative expression of genes such as cardiac IGF-2/H19, IGF-2R and AT1R through either an increase or decrease in DNA methylation or histone acetylation at specific loci. Furthermore, hypoxia and other intrauterine insults can also activate the IGF-1 receptor via IGF-1 and IGF-2, and the AT1 receptor via angiotensin signaling pathways; both of which can result in the phosphorylation of Akt and the activation of a range of downstream pathways. In turn, Akt activation can increase cardiac angiogenesis and cardiomyocyte apoptosis and promote a reversion of metabolism in postnatal life to a fetal phenotype, which involves increased reliance on glucose. Cardiac Akt can also be indirectly regulated by microRNAs and conversely can target microRNAs that will eventually affect other specific cardiac genes and proteins. This review aims to discuss our understanding of this complex network of interactions, which may help explain the link between low birth weight and the increased risk of cardiovascular disease in adult life.

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Y Yang, J Cao, W Xiong, J Zhang, Q Zhou, H Wei, C Liang, J Deng, T Li, S Yang, and L Xu

It has been documented that stress or glucocorticoids have conflicting effects on memory under different conditions. However, it is not fully understood why stress can either impair or enhance memory. Here, we have examined the performance of six age groups of Wistar rats in a water maze spatial task to evaluate the effects of stress under different conditions. We found that the impairment or enhancement effect of an 'elevated platform' (EP) stress on memory was dependent on previous stress experience and on age. EP stress impaired memory retrieval in water maze naive animals, but enhanced rather than impaired memory retrieval in young water maze stress-experienced animals. Furthermore, exogenously applied corticosterone or foot shock stress before water maze training prevented the impairment of memory retrieval that should be induced by treatment with corticosterone or foot shock before the 'probe trial'. Again, memory retrieval was enhanced in young animals under these conditions, and this enhancement can be prevented by the glucocorticoid receptor antagonist RU 38486. Thus, glucocorticoid receptor activation not only induced impairment of memory but also increased the capacity of young animals to overcome a later stress. The present findings suggest that the effect of stress on memory can be switched from impairment to enhancement dependent on both stress experience and age.