Sex differences in vasopressin V2 receptor expression and vasopressin-induced antidiuresis

The renal vasopressin V2 receptor (V2R) plays a critical role in physiological and pathophysiological processes associated with arginine vasopressin (AVP)-induced antidiuresis. Because clinical data suggests that females may be more prone to hyponatremia from AVP-mediated antidiuresis, we investigated whether there are sex differences in the expression and function of the renal V2R. In normal Sprague-Dawley rat kidneys, V2R mRNA and protein expression was 2.6- and 1.7-fold higher, respectively, in females compared with males. To investigate the potential physiological implications of this sex difference, we studied changes in urine osmolality induced by the AVP V2R agonist desmopressin. In response to different doses of desmopressin, there was a graded increase in urine osmolality and decrease in urine volume during a 24-h infusion. Females showed greater mean increases in urine osmolality and greater mean decreases in urine volume at 0.5 and 5.0 ng/h infusion rates. We also studied renal escape from antidiuresis produced by water loading in rats infused with desmopressin (5.0 ng/h). After 5 days of water loading, urine osmolality of both female and male rats escaped to the same degree physiologically, but V2R mRNA and protein in female kidneys was reduced to a greater degree (−63% and −73%, respectively) than in males (−32% and −48%, respectively). By the end of the 5-day escape period, renal V2R mRNA and protein expression were reduced to the same relative levels in males and females, thereby abolishing the sex differences in V2R expression seen in the basal state. Our results demonstrate that female rats express significantly more V2R mRNA and protein in kidneys than males, and that this results physiologically in a greater sensitivity to V2R agonist administration. The potential pathophysiological implications of these results are that females may be more susceptible to the development of dilutional hyponatremia because of a greater sensitivity to endogenously secreted AVP.

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Sex differences in ET-1 receptor expression and Ca2+ signaling in the IMCD

AJP Renal Physiology ◽

10.1152/ajprenal.00400.2013 ◽

2013 ◽

Vol 305 (8) ◽

pp. F1099-F1104 ◽

Cited By ~ 18

Author(s):

Chunhua Jin ◽

Joshua S. Speed ◽

Kelly A. Hyndman ◽

Paul M. O'Connor ◽

David M. Pollock

Keyword(s):

Sex Differences ◽

Radioligand Binding ◽

Collecting Duct ◽

Receptor Activation ◽

Receptor Expression ◽

Female Rats ◽

Male Rats ◽

Male And Female ◽

Male And Female Rats ◽

Intracellular Ca

The inner medullary collecting duct (IMCD) is the nephron segment with the highest production of endothelin-1 (ET-1) and the greatest expression of ET-1 receptors that function to adjust Na+ and water balance. We have reported that male rats have reduced natriuresis in response to direct intramedullary infusion of ET-1 compared with female rats. Our aim was to determine whether alterations of ET-1 receptor expression and downstream intracellular Ca2+ signaling within the IMCD could account for these sex differences. IMCDs from male and female rats were isolated for radioligand binding or microdissected for intracellular Ca2+ ([Ca2+]i) measurement by fluorescence imaging of fura-2 AM. IMCD from male and female rats had similar ETB expression (655 ± 201 vs. 567 ± 39 fmol/mg protein, respectively), whereas male rats had significantly higher ETA expression (436 ± 162 vs. 47 ± 29 fmol/mg protein, respectively; P < 0.05). The [Ca2+]i response to ET-1 was significantly greater in IMCDs from male compared with female rats (288 ± 52 vs. 118 ± 32 AUC, nM × 3 min, respectively; P < 0.05). In IMCDs from male rats, the [Ca2+]i response to ET-1 was significantly blunted by the ETA antagonist BQ-123 but not by the ETB antagonist BQ-788 (control: 137 ± 27; BQ-123: 53 ± 11; BQ-788: 84 ± 25 AUC, nM × 3 min; P < 0.05), consistent with greater ETA receptor function in male rats. These data demonstrate a sex difference in ETA receptor expression that results in differences in ET-1 Ca2+ signaling in IMCD. Since activation of ETA receptors is thought to oppose ETB receptor activation, enhanced ETA function in male rats could limit the natriuretic effects of ETB receptor activation.

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Developmental changes in plasma leptin and hypothalamic leptin receptor expression in the rat: peripubertal changes and the emergence of sex differences

Journal of Endocrinology ◽

10.1677/joe.0.1760313 ◽

2003 ◽

Vol 176 (3) ◽

pp. 313-319 ◽

Cited By ~ 51

Author(s):

JT Smith ◽

BJ Waddell

Keyword(s):

Sex Differences ◽

Mrna Expression ◽

Leptin Receptor ◽

Receptor Expression ◽

Developmental Changes ◽

Female Rats ◽

Male Rats ◽

Male And Female Rats ◽

Puberty Onset ◽

Plasma Leptin

Leptin, the peptide hormone product of the ob gene, regulates food intake and energy expenditure at the hypothalamic level via the long-form of the leptin receptor (Ob-Rb). Leptin also plays a key role in determining the onset of puberty, but there is controversy as to whether leptin provides a trigger for puberty or is a permissive signal. Thus, although leptin administration can advance puberty onset in rodents, circulating leptin appears stable across puberty. While these data suggest a permissive role for leptin in rat puberty, it is possible that a change in hypothalamic response to leptin (e.g. via increased Ob-Rb expression) could enhance leptin action and thus trigger puberty without a rise in circulating leptin. In the present study we assessed developmental changes in hypothalamic Ob-Rb mRNA and protein expression in female and male rats from late fetal to postpubertal life. Quantitative RT-PCR showed that Ob-Rb mRNA increased (P<0.05) by around fivefold from fetal to postpubertal life in both females and males. These increases in Ob-Rb mRNA expression were gradual, but did not increase significantly between postnatal day 30 (pre-puberty) and day 51 (post-puberty). By day 51, hypothalamic Ob-Rb mRNA expression was higher (P<0.05) in females relative to males. Hypothalamic Ob-Rb protein showed a comparable developmental pattern (approximate threefold increase from fetal to postpubertal life), although a significant increase (15%; P<0.05) was observed between days 30 and 51 in females. Plasma leptin levels exhibited a dynamic pattern in both male and female rats during the prepubertal period, characterised by a precipitous fall after birth, relative stability to day 5, then a rapid increase to a transient peak on day 12. Plasma leptin then remained unchanged from day 15 in female rats but increased in males after puberty, thus confirming the well-recognised sex difference in adult rat leptin levels. In conclusion, this study shows that developmental increases occur not only in plasma leptin but also in hypothalamic Ob-Rb expression, suggesting that both are likely to influence the timing of puberty onset. Moreover, our data show that sex differences in both hypothalamic Ob-Rb and plasma leptin emerge only after puberty.

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Analysis of sex differences in dietary copper-fructose interaction-induced alterations of gut microbial activity in relation to hepatic steatosis

Biology of Sex Differences ◽

10.1186/s13293-020-00346-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ming Song ◽

Fang Yuan ◽

Xiaohong Li ◽

Xipeng Ma ◽

Xinmin Yin ◽

...

Keyword(s):

Sex Differences ◽

Microbial Activity ◽

Hepatic Steatosis ◽

Female Rats ◽

Male Rats ◽

Calorie Intake ◽

Dietary Copper ◽

Male And Female ◽

Male And Female Rats ◽

Rrna Sequencing

Abstract Background Inadequate copper intake and increased fructose consumption represent two important nutritional problems in the USA. Dietary copper-fructose interactions alter gut microbial activity and contribute to the development of nonalcoholic fatty liver disease (NAFLD). The aim of this study is to determine whether dietary copper-fructose interactions alter gut microbial activity in a sex-differential manner and whether sex differences in gut microbial activity are associated with sex differences in hepatic steatosis. Methods Male and female weanling Sprague-Dawley (SD) rats were fed ad libitum with an AIN-93G purified rodent diet with defined copper content for 8 weeks. The copper content is 6 mg/kg and 1.5 mg/kg in adequate copper diet (CuA) and marginal copper diet (CuM), respectively. Animals had free access to either deionized water or deionized water containing 10% fructose (F) (w/v) as the only drink during the experiment. Body weight, calorie intake, plasma alanine aminotransferase, aspartate aminotransferase, and liver histology as well as liver triglyceride were evaluated. Fecal microbial contents were analyzed by 16S ribosomal RNA (16S rRNA) sequencing. Fecal and cecal short-chain fatty acids (SCFAs) were determined by gas chromatography-mass spectrometry (GC-MS). Results Male and female rats exhibit similar trends of changes in the body weight gain and calorie intake in response to dietary copper and fructose, with a generally higher level in male rats. Several female rats in the CuAF group developed mild steatosis, while no obvious steatosis was observed in male rats fed with CuAF or CuMF diets. Fecal 16S rRNA sequencing analysis revealed distinct alterations of the gut microbiome in male and female rats. Linear discriminant analysis (LDA) effect size (LEfSe) identified sex-specific abundant taxa in different groups. Further, total SCFAs, as well as, butyrate were decreased in a more pronounced manner in female CuMF rats than in male rats. Of note, the decreased SCFAs are concomitant with the reduced SCFA producers, but not correlated to hepatic steatosis. Conclusions Our data demonstrated sex differences in the alterations of gut microbial abundance, activities, and hepatic steatosis in response to dietary copper-fructose interaction in rats. The correlation between sex differences in metabolic phenotypes and alterations of gut microbial activities remains elusive.

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Vulnerability factors for mephedrone-induced conditioned place preference in rats—the impact of sex differences, social-conditioning and stress

Psychopharmacology ◽

10.1007/s00213-021-05910-y ◽

2021 ◽

Author(s):

Olga Wronikowska ◽

Maria Zykubek ◽

Łukasz Kurach ◽

Agnieszka Michalak ◽

Anna Boguszewska-Czubara ◽

...

Keyword(s):

Sex Differences ◽

Conditioned Place Preference ◽

Low Dose ◽

Social Factor ◽

Place Preference ◽

Female Rats ◽

Male Rats ◽

Social Conditioning ◽

Male And Female Rats ◽

The Impact

Abstract Rationale Mephedrone is a frequently overused drug of abuse that belongs to the group of novel psychoactive substances. Although its mechanism of action, as well as toxic and psychoactive effects, has been widely studied, the role of different factors that could contribute to the increased vulnerability to mephedrone abuse is still poorly understood. Objectives The aim of the presented study was to assess the impact of several factors (sex differences, social-conditioning, and chronic mild unpredictable stress — CMUS) on the liability to mephedrone-induced reward in Wistar rats. Methods The rewarding effects of mephedrone in male and female rats were assessed using the conditioned place preference (CPP) procedure. Furthermore, the impact of social factor and stress was evaluated in male rats using social-CPP and CMUS-dependent CPP, respectively. Results Mephedrone induced classic-CPP in female (10 mg/kg), as well as in male (10 and 20 mg/kg) rats. However, the impact of mephedrone treatment during social-CPP was highly dose-dependent as the rewarding effects of low dose of mephedrone (5 mg/kg; non-active in classic-CPP) were potentiated when administered during social-conditioning. Interestingly, social-conditioning with a higher dose of 20 mg/kg (that induced classic-CPP) was able to reverse these effects. Finally, CMUS potentiated rewarding effects of a low dose of mephedrone (5 mg/kg) and increased the level of corticosterone in rats’ prefrontal cortex and hippocampus. Conclusions Altogether, the presented results give new insight into possible factors underlying the vulnerability to mephedrone abuse and can serve as a basis for further studies assessing mechanisms underlying observed effects.

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Novel regulation of renal gluconeogenesis by Atp6ap2 in response to high fat diet via PGC1-α/AKT-1 pathway

Scientific Reports ◽

10.1038/s41598-021-90952-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Safia Akhtar ◽

Silas A. Culver ◽

Helmy M. Siragy

Keyword(s):

Protein Expression ◽

High Fat Diet ◽

Normal Diet ◽

Receptor Expression ◽

Wild Type ◽

High Fat ◽

Renal Gluconeogenesis ◽

Mrna And Protein Expression ◽

Polymerase Chain ◽

Renal Expression

AbstractRecent studies suggested that renal gluconeogenesis is substantially stimulated in the kidney in presence of obesity. However, the mechanisms responsible for such stimulation are not well understood. Recently, our laboratory demonstrated that mice fed high fat diet (HFD) exhibited increase in renal Atp6ap2 [also known as (Pro)renin receptor] expression. We hypothesized that HFD upregulates renal gluconeogenesis via Atp6ap2-PGC-1α and AKT pathway. Using real-time polymerase chain reaction, western blot analysis and immunostaining, we evaluated renal expression of the Atp6ap2 and renal gluconeogenic enzymes, PEPCK and G6Pase, in wild type and inducible nephron specific Atp6ap2 knockout mice fed normal diet (ND, 12 kcal% fat) or a high-fat diet (HFD, 45 kcal% fat) for 8 weeks. Compared with ND, HFD mice had significantly higher body weight (23%) (P < 0.05), renal mRNA and protein expression of Atp6ap2 (39 and 35%), PEPCK (44 and 125%) and G6Pase (39 and 44%) respectively. In addition, compared to ND, HFD mice had increased renal protein expression of PGC-1α by 32% (P < 0.05) and downregulated AKT by 33% (P < 0.05) respectively in renal cortex. Atp6ap2-KO abrogated these changes in the mice fed HFD. In conclusion, we identified novel regulation of renal gluconeogenesis by Atp6ap2 in response to high fat diet via PGC1-α/AKT-1 pathway.

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Sex Differences in Escalated Methamphetamine Self-Administration and Altered Gene Expression Associated With Incubation of Methamphetamine Seeking

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyz050 ◽

2019 ◽

Vol 22 (11) ◽

pp. 710-723 ◽

Cited By ~ 8

Author(s):

Atul P Daiwile ◽

Subramaniam Jayanthi ◽

Bruce Ladenheim ◽

Michael T McCoy ◽

Christie Brannock ◽

...

Keyword(s):

Sex Differences ◽

Nucleus Accumbens ◽

Fixed Ratio ◽

Female Rats ◽

Male Rats ◽

Mrna Levels ◽

Self Administration ◽

Male And Female ◽

Orexin Receptors ◽

Male And Female Rats

Abstract Background Methamphetamine (METH) use disorder is prevalent worldwide. There are reports of sex differences in quantities of drug used and relapses to drug use among individuals with METH use disorder. However, the molecular neurobiology of these potential sex differences remains unknown. Methods We trained rats to self-administer METH (0. 1 mg/kg/infusion, i.v.) on an fixed-ratio-1 schedule for 20 days using two 3-hour daily METH sessions separated by 30-minute breaks. At the end of self-administration training, rats underwent tests of cue-induced METH seeking on withdrawal days 3 and 30. Twenty-four hours later, nucleus accumbens was dissected and then used to measure neuropeptide mRNA levels. Results Behavioral results show that male rats increased the number of METH infusions earlier during self-administration training and took more METH than females. Both male and female rats could be further divided into 2 phenotypes labeled high and low takers based on the degree of escalation that they exhibited during the course of the METH self-administration experiment. Both males and females exhibited incubation of METH seeking after 30 days of forced withdrawal. Females had higher basal mRNA levels of dynorphin and hypocretin/orexin receptors than males, whereas males expressed higher vasopressin mRNA levels than females under saline and METH conditions. Unexpectedly, only males showed increased expression of nucleus accumbens dynorphin after METH self-administration. Moreover, there were significant correlations between nucleus accumbens Hcrtr1, Hcrtr2, Crhr2, and Avpr1b mRNA levels and cue-induced METH seeking only in female rats. Conclusion Our results identify some behavioral and molecular differences between male and female rats that had self-administered METH. Sexual dimorphism in responses to METH exposure should be considered when developing potential therapeutic agents against METH use disorder.

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

Acta Veterinaria Hungarica ◽

10.1556/avet.2012.060 ◽

2013 ◽

Vol 61 (1) ◽

pp. 85-98 ◽

Cited By ~ 8

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.

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Similar levels of emotional contagion in male and female rats

10.1101/857094 ◽

2019 ◽

Author(s):

Yingying Han ◽

Bo Sichterman ◽

Maria Carrillo ◽

Valeria Gazzola ◽

Christian Keysers

Keyword(s):

Sex Differences ◽

Social Life ◽

Emotional Contagion ◽

Female Rats ◽

Male Rats ◽

Neural Basis ◽

Male And Female Rats ◽

Danger Detection ◽

Rats And Mice ◽

Shed Light

AbstractEmotional contagion, the ability to feel what other individuals feel, is thought to be an important element of social life. In humans, emotional contagion has been shown to be stronger in women than men. Emotional contagion has been shown to exist also in rodents, and a growing number of studies explore the neural basis of emotional contagion in male rats and mice. These studies promise to shed light on the mechanisms that might go astray in psychiatric disorders characterized by dysfunctions of emotional contagion and empathy. Here we explore whether there are sex differences in emotional contagion in rats. We use an established paradigm in which a demonstrator rat receives footshocks while freezing is measured in both the demonstrator and an observer rat, which can hear, smell and see each other. By comparing pairs of male rats with pairs of female rats, we find (i) that female demonstrators freeze less when submitted to footshocks, but that (ii) the emotional contagion response, i.e. the degree of influence across the rats, does not depend on the sex of the rats. This was true whether emotional contagion was quantified based on the slope of a regression linking demonstrator and observer average freezing, or on Granger causality estimates of moment-to-moment freezing. The lack of sex differences in emotional contagion is compatible with an interpretation of emotional contagion as serving selfish danger detection.

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Risk-based Decision Making in Rats: Modulation by Sex and Amphetamine

10.1101/2020.03.09.981563 ◽

2020 ◽

Author(s):

Dannia Islas-Preciado ◽

Steven R. Wainwright ◽

Julia Sniegocki ◽

Stephane E. Lieblich ◽

Shunya Yagi ◽

...

Keyword(s):

Decision Making ◽

Sex Differences ◽

Gonadal Hormones ◽

Risky Choice ◽

Female Rats ◽

Male Rats ◽

Risky Decision Making ◽

Risky Decision ◽

17Β Estradiol ◽

Males And Females

AbstractDecision-making is a complex process essential to daily adaptation in many species. Risk is an inherent aspect of decision-making and it is influenced by gonadal hormones. Testosterone and 17β-estradiol may modulate decision making and impact the mesocorticolimbic dopamine pathway. Here, we explored sex differences, the effect of gonadal hormones and the dopamine agonist amphetamine on risk-based decision making. Intact or gonadectomised (GDX) male and female rats underwent to a probabilistic discounting task. High and low doses of testosterone propionate (1.0 or 0.2 mg) and 17β-estradiol benzoate (0.3 μg) were administered to assess acute effects on risk-based decision making. After 3-days of washout period, intact and GDX rats received high or low (0.5 or 0.125 mg/kg) doses of amphetamine and re-tested in the probabilistic discounting task. Under baseline conditions, males made more risky choices during probability discounting compared to female rats, particularly in the lower probability blocks, but GDX did not influence risky choice. The high, but not the low dose, of testosterone modestly reduced risky decision making in GDX male rats. Conversely, 17β-estradiol had no significant effect on risky choice regardless of GDX status in either sex. Lastly, a higher dose of amphetamine increased risky decision making in both intact males and females, but had no effect in GDX rats. These findings demonstrated sex differences in risk-based decision making, with males showing a stronger bias towards larger, uncertain rewards. GDX status influenced the effects of amphetamine, suggesting different dopaminergic regulation in risk-based choices among males and females.

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Abstract P317: Sex Differences in the Hemodynamic and Sympathetic Responses to Centrally Administered Tumor Necrosis Factor-α in Rats

Hypertension ◽

10.1161/hyp.70.suppl_1.p317 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Shun-Guang Wei ◽

Yang Yu ◽

Robert B Felder

Keyword(s):

Heart Failure ◽

Sex Differences ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Female Rats ◽

Male Rats ◽

Tnf Α ◽

Estrogen Effect ◽

Factor Α ◽

Necrosis Factor

Introduction: Accumulating evidence indicates that sex differences exist in the clinical and experimental outcomes of various cardiovascular diseases. In addition to its protective effect on renin-angiotensin system activity, estrogen has an anti-inflammatory influence. The central actions of pro-inflammatory cytokines (PICs) contribute significantly to cardiovascular and autonomic dysfunction in hypertension and heart failure. In male adult rat, central administration of PICs induces substantial increases in blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA), and blocking PICs reduces sympathetic excitation in experimental models of hypertension and heart failure. Whether PICs have similar central sympatho-excitatory effects in the female rat remains unknown. Hypothesis: We hypothesized that female rats may be protected from the central cardiovascular and autonomic effects of PICs. Methods: Urethane anesthetized male and female Sprague Dawley rats (10-12 weeks) underwent an intracerebrovascular (ICV) injection of the prototypical PIC tumor necrosis factor-α (TNF-α, 100 ng). BP (mmHg), HR (beats/min) and RSNA (% change) responses were continuously recorded for 4-5 hours. Results: In male rats (n=6), ICV TNF-α induced a dramatic and long-lasting increase (*p<0.001 vs. baseline) in BP (23.1 ± 2.5*), HR (82 ± 8*) and RSNA (109.5 ± 4.3 %*), that began within 20-30 mins and peaked at 90-120 mins after ICV injection. In the female rats (n=6), ICV TNF-α elicited significantly (p<0.05) smaller increases (*p<0.001 vs. baseline) in BP (14.8 ± 1.8*), HR (55 ± 6*) and RSNA (78.5 ± 6.3*), compared with the male rats. Conclusion: These data demonstrate a sex difference in the cardiovascular and sympathetic responses to centrally administered PICs. Whether the observed differences can be explained by an estrogen effect on TNF-α signaling per se or by an estrogen effect on TNF-α-induced renin-angiotensin activity remains to be determined. However, a reduced response of female rats to central inflammation may be an important contributor to sex differences in pathophysiology of hypertension and heart failure.

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