scholarly journals The salivary protein BPIFA2 differentially regulates sodium preference and blood pressure in male and female mice

2020 ◽  
Vol 1 ◽  
Author(s):  
Sven-Ulrik Gorr
Keyword(s):  
Blood Pressure ◽  
Knockout Mice ◽  
Salivary Protein ◽  
Binding Activity ◽  
Wild Type ◽  
Male And Female ◽  
Knockout Mouse Model ◽  
Spontaneously Hypertensive ◽  
Female Mice ◽  
Lps Binding

AbstractBPIFA2 (PSP, SPLUNC2, C20orf70) is a major salivary protein of uncertain physiological function. BPIFA2 is downregulated in salivary glands of spontaneously hypertensive rats, pointing to a role in blood pressure regulation. This study used a novel Bpifa2 knockout mouse model to test the role of BPIFA2 in sodium preference and blood pressure. Blood pressure did not differ between wild-type male and female mice but was significantly lower in male knockout mice compared to male wild-type mice. In contrast, blood pressure was increased in female knockout mice compared to female wild-type mice. Female wild-type mice showed a significant preference for 0.9% saline compared to male mice. This difference was reduced in the knockout mice. BPIFA2 is an LPS-binding protein but it remains to be determined if the reported effects are mediated by the LPS-binding activity of BPIFA2.

scholarly journals Tpcn2 knockout mice have improved insulin sensitivity and are protected against high-fat diet-induced weight gain

2018 ◽  
Vol 50 (8) ◽  
pp. 605-614
Author(s):  
Hong He ◽  
Katie Holl ◽  
Sarah DeBehnke ◽  
Chay Teng Yeo ◽  
Polly Hansen ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Male And Female ◽  
Female Mice

Type 2 diabetes is a complex disorder affected by multiple genes and the environment. Our laboratory has shown that in response to a glucose challenge, two-pore channel 2 ( Tpcn2) knockout mice exhibit a decreased insulin response but normal glucose clearance, suggesting they have improved insulin sensitivity compared with wild-type mice. We tested the hypothesis that improved insulin sensitivity in Tpcn2 knockout mice would protect against the negative effects of a high fat diet. Male and female Tpcn2 knockout (KO), heterozygous (Het), and wild-type (WT) mice were fed a low-fat (LF) or high-fat (HF) diet for 24 wk. HF diet significantly increases body weight in WT mice relative to those on the LF diet; this HF diet-induced increase in body weight is blunted in the Het and KO mice. Despite the protection against diet-induced weight gain, however, Tpcn2 KO mice are not protected against HF-diet-induced changes in glucose or insulin area under the curve during glucose tolerance tests in female mice, while HF diet has no significant effect on glucose tolerance in the male mice, regardless of genotype. Glucose disappearance during an insulin tolerance test is augmented in male KO mice, consistent with our previous findings suggesting enhanced insulin sensitivity in these mice. Male KO mice exhibit increased fasting plasma total cholesterol and triglyceride concentrations relative to WT mice on the LF diet, but this difference disappears in HF diet-fed mice where there is increased cholesterol and triglycerides across all genotypes. These data demonstrate that knockout of Tpcn2 may increase insulin action in male, but not female, mice. In addition, both male and female KO mice are protected against diet-induced weight gain, but this protection is likely independent from glucose tolerance, insulin sensitivity, and plasma lipid levels.

scholarly journals Differential effects of Mas receptor deficiency on cardiac function and blood pressure in obese male and female mice

2017 ◽  
Vol 312 (3) ◽  
pp. H459-H468 ◽  
Author(s):  
Yu Wang ◽  
Robin Shoemaker ◽  
David Powell ◽  
Wen Su ◽  
Sean Thatcher ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Ang Ii ◽  
Wild Type ◽  
Male And Female ◽  
Reduced Ejection Fraction ◽  
Female Mice ◽  
Induced Hypertension ◽  
Blood Pressures

Angiotensin-(1–7) [ANG-(1–7)] acts at Mas receptors (MasR) to oppose effects of angiotensin II (ANG II). Previous studies demonstrated that protection of female mice from obesity-induced hypertension was associated with increased systemic ANG-(1–7), whereas male obese hypertensive mice exhibited increased systemic ANG II. We hypothesized that MasR deficiency ( MasR−/−) augments obesity-induced hypertension in males and abolishes protection of females. Male and female wild-type ( MasR+/+) and MasR−/− mice were fed a low-fat (LF) or high-fat (HF) diet for 16 wk. MasR deficiency had no effect on obesity. At baseline, male and female MasR−/− mice had reduced ejection fraction (EF) and fractional shortening than MasR+/+ mice. Male, but not female, HF-fed MasR+/+ mice had increased systolic and diastolic (DBP) blood pressures compared with LF-fed controls. In HF-fed females, MasR deficiency increased DBP compared with LF-fed controls. In contrast, male HF-fed MasR−/− mice had lower DBP than MasR+/+ mice. We quantified cardiac function after 1 mo of HF feeding in males of each genotype. HF-fed MasR−/− mice had higher left ventricular (LV) wall thickness than MasR+/+ mice. Moreover, MasR+/+, but not MasR−/−, mice displayed reductions in EF from HF feeding that were reversed by ANG-(1–7) infusion. LV fibrosis was reduced in HF-fed MasR+/+ but not MasR−/− ANG-(1–7)-infused mice. These results demonstrate that MasR deficiency promotes obesity-induced hypertension in females. In males, HF feeding reduced cardiac function, which was restored by ANG-(1–7) in MasR+/+ but not MasR−/− mice. MasR agonists may be effective therapies for obesity-associated cardiovascular conditions. NEW & NOTEWORTHY MasR deficiency abolishes protection of female mice from obesity-induced hypertension. Male MasR-deficient obese mice have reduced blood pressure and declines in cardiac function. ANG-(1–7) infusion restores obesity-induced cardiac dysfunction of wild-type, but not MasR-deficient, male mice. MasR agonists may be cardioprotective in obese males and females.

scholarly journals Deficiency of MicroRNA-181a Results in Transcriptome-Wide Cell Specific Changes in the Kidney that Lead to Elevated Blood Pressure and Salt Sensitivity

2021 ◽  
Author(s):  
Madeleine R. Paterson ◽  
Kristy L. Jackson ◽  
Malathi I. Dona ◽  
Gabriella E. Farrugia ◽  
Bruna Visniauskas ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Knockout Mice ◽  
Molecular Mechanisms ◽  
Salt Sensitivity ◽  
Juxtaglomerular Cells ◽  
Renal Cells ◽  
Wild Type ◽  
Knockout Mouse Model

AbstractMicroRNA miR-181a is down-regulated in the kidneys of hypertensive patients and hypertensive mice. In vitro, miR-181a is a posttranslational inhibitor of renin expression, but pleiotropic mechanisms by which miR-181a may influence blood pressure (BP) are unknown. Here we determined whether deletion of miR-181a/b-1 in vivo changes BP and the molecular mechanisms involved at the single-cell level. We developed a knockout mouse model lacking miR-181a/b-1 genes using CRISPR/Cas9 technology. Radio-telemetry probes were implanted in twelve-week-old C57BL/6J wild-type and miR-181a/b-1 knockout mice. Systolic and diastolic BP were 4-5mmHg higher in knockout compared with wild-type mice over 24-hours (P<0.01). Compared with wild-type mice, renal renin was higher in the juxtaglomerular cells of knockout mice. BP was similar in wild-type mice on a high (3.1%) versus low (0.3%) sodium diet (+0.4±0.8mmHg) but knockout mice showed salt sensitivity (+3.3±0.8mmHg, P<0.001). Since microRNAs can target several mRNAs simultaneously, we performed single-nuclei RNA-sequencing in 6,699 renal cells. We identified 12 distinct types of renal cells, all of which had genes that were dysregulated. This included genes involved in renal fibrosis and inflammation such as Stat4, Col4a1, Cd81, Flt3l, Cxcl16, Smad4. We observed up-regulation of pathways related to the immune system, inflammatory response, reactive oxygen species and nerve development, consistent with higher tyrosine hydroxylase. In conclusion, downregulation of the miR-181a gene led to increased BP and salt sensitivity in mice. This is likely due to an increase in renin expression in juxtaglomerular cells, as well as microRNA-driven pleiotropic effects impacting renal pathways associated with hypertension.

scholarly journals Role of IL-6 and TNF in thermoregulation and survival during sepsis in mice

1998 ◽  
Vol 275 (1) ◽  
pp. R269-R277 ◽  
Author(s):  
Lisa R. Leon ◽  
Andrew A. White ◽  
Matthew J. Kluger
Keyword(s):  
Knockout Mice ◽  
Gene Knockout ◽  
Cecal Ligation ◽  
Wild Type ◽  
Profound Hypothermia ◽  
Male And Female ◽  
Female Mice ◽  
Tnf Α ◽  
Gene Knockout Mice

Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) have been implicated as key mediators in inflammation, morbidity, and mortality associated with sepsis. We examined the role of IL-6 and TNF-α signaling on hypothermia, fever, cachexia, anorexia, and survival during sepsis induced by cecal ligation and puncture (CLP) in male and female gene knockout mice. Male wild-type mice developed an initial hypothermia and subsequent fever during sepsis. Male IL-6 knockout mice did not develop fever; rather, they maintained a profound hypothermia during sepsis. Male TNF p55/p75 receptor (TNFR) knockout mice had attenuated hypothermia, but developed a virtually identical fever as wild-type mice. Cachexia did not differ between male wild-type and IL-6 or TNFR knockout mice, whereas anorexia was prolonged in IL-6 knockout mice. Due to the rapid lethality of sepsis in female mice, survival was the only variable we were able to statistically compare among female genotypes. Female wild-type mice had significantly decreased survival compared with male wild-type mice. Survival was significantly enhanced in male and female TNFR knockout mice compared with their wild-type controls. Lack of IL-6 did not affect male or female lethality. These data support the hypothesis that IL-6 is a key mediator of fever and food intake, whereas TNF is responsible for the initial hypothermia and lethality of sepsis in both sexes of mice. The enhanced lethality of CLP-treated female mice supports a role for sex steroids during sepsis.

Abstract 096: Leptin and High Salt Diet Induce Greater Increases in Blood Pressure in Female than Male Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Jessica L Faulkner ◽  
Eric J Belin de Chantemele
Keyword(s):  
Blood Pressure ◽  
Recovery Period ◽  
Pressure Rise ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Male And Female ◽  
Female Mice ◽  
Males And Females ◽  
Blood Pressure Responses

Recent studies by our group demonstrated that leptin is a direct regulator of aldosterone secretion and increases blood pressure via sex-specific mechanisms involving leptin-mediated activation of the aldosterone-mineralocorticoid receptor signaling pathway in females and sympatho-activation in males. Although it is well accepted that females secrete more leptin and aldosterone than males, it is unknown whether leptin infusion raises blood pressure similarly in male and female mice and whether higher aldosterone levels sensitize females to salt-induced hypertension. We hypothesized that female mice would be more sensitive to leptin than males and also have a potentiated blood pressure rise in response to high salt diet compared to males. Male and female Balb/C mice were implanted with radiotelemeters for continuous measurement of mean arterial pressure (MAP) at 10 weeks of age. MAP was measured for seven days prior to feeding with a high-salt diet (HS, 4%NaCl) for seven days. Following a recovery period, animals were then implanted with osmotic minipumps containing leptin (0.9mg/kg/day) recorded for seven days. Baseline MAP was similar between males and females (101.3±2.9 vs 99.3±3.7 mmHg, n=4 and 5, respectively), however, HS diet resulted in a greater MAP increase in females (15.0±2.6 mmHg) compared to males (3.1±4.5 mmHg, P<0.05). MAP with leptin treatment was increased with leptin in females moreso than in males, however, this did not reach significance (6.8±5.8 vs 1.8±5.9 mmHg, respectively). This potential sex difference in blood pressure responses to leptin was not associated with changes in body weight (0.07±0.44 vs -0.22±0.2 g, respectively) nor changes in blood glucose (-19.67±15.06 vs -15.4±11.4 mg/dl, respectively) in males and females in response to leptin. In summary, female mice are more sensitive to HS diet-induced blood pressure increases than males. Females may be more sensitive to leptin-mediated blood pressure increases than males. Further investigation is needed to determine whether these sex differences in blood pressure responses to HS diet and leptin are mediated by aldosterone or other mechanisms.

scholarly journals NPY Deficiency Prevents Postmenopausal Adiposity by Augmenting Estradiol-Mediated Browning

2018 ◽  
Vol 75 (6) ◽  
pp. 1042-1049
Author(s):  
Seongjoon Park ◽  
Erkhembayar Nayantai ◽  
Toshimitsu Komatsu ◽  
Hiroko Hayashi ◽  
Ryoichi Mori ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Fat Metabolism ◽  
Male Mice ◽  
Wild Type ◽  
Male And Female ◽  
Female Mice ◽  
Age Related ◽  
Promising Target ◽  
Intracellular Mechanism

Abstract The orexigenic hormone neuropeptide Y (NPY) plays a pivotal role in the peripheral regulation of fat metabolism. However, the mechanisms underlying the effects of sex on NPY function have not been extensively analyzed. In this study, we examined the effects of NPY deficiency on fat metabolism in male and female mice. Body weight was slightly decreased, whereas white adipose tissue (WAT) mass was significantly decreased as the thermogenic program was upregulated in NPY-/- female mice compared with that in wild-type mice; these factors were not altered in response to NPY deficiency in male mice. Moreover, lack of NPY resulted in an increase in luteinizing hormone (LH) expression in the pituitary gland, with concomitant activation of the estradiol-mediated thermogenic program in inguinal WAT, and alleviated age-related modification of adiposity in female mice. Taken together, these data revealed a novel intracellular mechanism of NPY in the regulation of fat metabolism and highlighted the sexual dimorphism of NPY as a promising target for drug development to reduce postmenopausal adiposity.

Abstract 7: Angiotensin II Type 2 Receptor Deficiency Increases Renal ACE/ACE2 Ratio-Ang II-AT1R Expression In Male but not in Female Mice

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Quaisar Ali ◽  
Yonnie Wu ◽  
Tadashi Inagami ◽  
Tahir Hussain
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Angiotensin Ii ◽  
Renin Activity ◽  
Ang Ii ◽  
Male And Female ◽  
Female Mice ◽  
Gender Specific

Angiotensin II acting via Angiotensin II type 2 receptors (AT2Rs) is believed to be protective against blood pressure increase and affects renal function under pathophysiological condition. Recently we have observed that stimulation of AT2Rs in male obese Zucker rats has shifted the two opposing arms of renin angiotensin system (RAS) i.e. ACE-Ang II-AT1 vs ACE2/Ang-(1-7)-Mas. Evidence suggests that estrogen regulates RAS, including AT2R in female mice. We hypothesized that AT2R has a gender specific regulation of RAS. In the present study, we investigated the role of AT2Rs in regulating RAS components in male and female mice. Kidney cortex from AT2R knockout (AT2RKO) male and female mice and wild type (WT) with similar background (C57BL/6) of 20 weeks of age were used in the study. The cortical ACE expression (ng ACE/μg tissue) was significantly increased in AT2RKO mice (3±0.02) compared to WT males (1.9±0.02). LC/MS analysis of cortical tissue revealed that Ang II was also significantly increased in AT2RKO mice (WT: 31±3, AT2RKO: 47±3 fmoles/mg tissue). Deletion of AT2R significantly increased AT1R (204%, 204 of 100) expression and had no effect on renin activity compared to WT males. The cortical expression of ACE2 activity (WT: 113±8, AT2RKO: 40±11, RFU/min), Ang-(1-7) levels (WT: 7.3±1.4, AT2RKO: 3±0.8 fmoles/mg tissue) and Mas receptor (AT2RKO: 54±15, % of WT) was significantly decreased in AT2RKO males compared to WT. The cortical expression of the AT2R and MasR was 2-fold greater in WT females compared to WT male. The renin activity (WT: 32±2, AT2RKO: 21±0.3, RFU/min) and MasR expression (WT: 187.5±55, AT2KO: 47±9) was significantly decreased in AT2RKO females compared to the female WT. Interestingly, Ang-(1-7) level (WT: 5.7±0.7, AT2RKO 2.6±0.7 fmoles/mg tissue) was decreased but no changes in ACE or ACE2 activity was observed in AT2KO females compared to their WT, suggesting a role of non-ACE2 pathway. This study suggests that AT2R regulates ACE/ACE2 ratio-Ang II-AT1R expression negatively only in males, whereas in females, it regulates Ang-(1-7) potentially via non-ACE2 pathway. Such changes indicate a gender specific mechanisms potentially associated with AT2R-mediated regulation of renal function and blood pressure control.

scholarly journals Nuclear Activation Function 2 Estrogen Receptor α Attenuates Arterial and Renal Alterations Due to Aging and Hypertension in Female Mice

2020 ◽  
Vol 9 (5) ◽  
Author(s):  
Emmanuel Guivarc'h ◽  
Julie Favre ◽  
Anne‐Laure Guihot ◽  
Emilie Vessières ◽  
Linda Grimaud ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Estrogen Receptor ◽  
Angiotensin Ii ◽  
Systolic Blood Pressure ◽  
Vascular Reactivity ◽  
Nuclear Gene ◽  
Estrogen Receptor Α ◽  
Protective Effects ◽  
Wild Type ◽  
Female Mice

Background The cardiovascular protective effects of estrogens in premenopausal women depend mainly on estrogen receptor α (ERα). ERα activates nuclear gene transcription regulation and membrane‐initiated signaling. The latter plays a key role in estrogen‐dependent activation of endothelial NO synthase. The goal of the present work was to determine the respective roles of the 2 ERα activities in endothelial function and cardiac and kidney damage in young and old female mice with hypertension, which is a major risk factor in postmenopausal women. Methods and Results Five‐ and 18‐month‐old female mice lacking either ERα (ERα −/− ), the nuclear activating function AF2 of ERα (AF2°), or membrane‐located ERα (C451A) were treated with angiotensin II (0.5 mg/kg per day) for 1 month. Systolic blood pressure, left ventricle weight, vascular reactivity, and kidney function were then assessed. Angiotensin II increased systolic blood pressure, ventricle weight, and vascular contractility in ERα −/− and AF2° mice more than in wild‐type and C451A mice, independent of age. In both the aorta and mesenteric resistance arteries, angiotensin II and aging reduced endothelium‐dependent relaxation in all groups, but this effect was more pronounced in ERα −/− and AF2° than in the wild‐type and C451A mice. Kidney inflammation and oxidative stress, as well as blood urea and creatinine levels, were also more pronounced in old hypertensive ERα −/− and AF2° than in old hypertensive wild‐type and C451A mice. Conclusions The nuclear ERα‐AF2 dependent function attenuates angiotensin II–dependent hypertension and protects target organs in aging mice, whereas membrane ERα signaling does not seem to play a role.

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