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3. Genetic Deletion of β-Arrestin 2 From the Subfornical Organ and Other Periventricular Nuclei in the Brain Alters Fluid Homeostasis and Blood Pressure

Author

Mathieu, Natalia M., primary, Tan, Eden E., additional, Reho, John J., additional, Brozoski, Daniel T., additional, Muskus, Patricia C., additional, Lu, Ko-Ting, additional, Wackman, Kelsey K., additional, Grobe, Justin L., additional, Nakagawa, Pablo, additional, and Sigmund, Curt D., additional

Published
2024
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5. Modulatory effects of estrous cycle on ingestive behaviors and energy balance in young adult C57BL/6J mice maintained on a phytoestrogen-free diet.

Author

Reho, John J., Muskus, Patricia C., Bennett, Darby M., Grobe, Connie C., Burnett, Colin M. L., Nakagawa, Pablo, Segar, Jeffrey L., Sigmund, Curt D., and Grobe, Justin L.

Subjects
LABORATORY mice, YOUNG adults, ESTRUS, ELEMENTAL diet, SOY proteins, ENERGY consumption
Abstract

The estrous cycle is known to modify food, fluid, and electrolyte intake behaviors and energy homeostasis in various species, in part through fluctuations in estrogen levels. Simultaneously, commonly commercially available rodent dietary formulations greatly vary in soy protein content, and thereby the delivery of biologically active phytoestrogens. To explore the interactions among the estrous cycle, sodium, fluid, and caloric seeking behaviors, and energy homeostasis, young adult C57BL/6J female mice were maintained on a soy protein-free 2920x diet and provided water, or a choice between water and 0.15 mol/L NaCl drink solution. Comprehensive metabolic phenotyping was performed using a multiplexed Promethion (Sable Systems International) system, and estrous stages were determined via daily vaginal cytology. When provided food and water, estrous cycling had no major modulatory effects on intake behaviors or energy balance. When provided a saline solution drink choice, significant modulatory effects of the transition from diestrus to proestrus were observed upon fluid intake patterning, locomotion, and total energy expenditure. Access to saline increased total daily sodium consumption and aspects of energy expenditure, but these effects were not modified by the estrous stage. Collectively, these results indicate that when supplied a phytoestrogen-free diet, the estrous cycle has minor modulatory effects on ingestive behaviors and energy balance in C57BL/6J mice that are sensitive to sodium supply. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Insights Into the Role of Angiotensin-II AT1 Receptor-Dependent β-Arrestin Signaling in Cardiovascular Disease.

Author

Mathieu, Natalia M., Nakagawa, Pablo, Grobe, Justin L., and Sigmund, Curt D.

Abstract

β-arrestins are a family of intracellular signaling proteins that play a key role in regulating the activity of G proteincoupled receptors. The angiotensin-II type 1 receptor is an important G protein-coupled receptor involved in the regulation of cardiovascular function and has been implicated in the progression of cardiovascular diseases. In addition to canonical G protein signaling, G protein-coupled receptors including the angiotensin-II type 1 receptor can signal via β-arrestin. Dysregulation of β-arrestin signaling has been linked to several cardiovascular diseases including hypertension, atherosclerosis, and heart failure. Understanding the role of β-arrestins in these conditions is critical to provide new therapeutic targets for the treatment of cardiovascular disease. In this review, we will discuss the beneficial and maladaptive physiological outcomes of angiotensin-II type 1 receptor-dependent β-arrestin activation in different cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Abstract 060: Conditional Deletion Of Renin In The Mouse Brain Results In Cardiovascular And Respiratory Abnormalities In Response To Hypoxia Or Autonomic Blockade

Author

Fekete, Eva M, primary, Muskus Veitia, Patricia, additional, Mathieu, Natalia, additional, Brozoski, Daniel, additional, Golosova, Daria, additional, Gomez, Javier, additional, Mouradian, Gary, additional, Hodges, Matthew, additional, Grobe, Justin L, additional, Sigmund, Curt D, additional, and Nakagawa, Pablo, additional

Published
2023
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11. Cardiometabolic Effects of DOCA-Salt in Mice Depend on Ambient Temperature

Author

Grobe, Connie C., primary, Reho, John J., additional, Brown-Williams, Daeleon, additional, Ziegler, Alisha A., additional, Mathieu, Natalia M., additional, Lawton, Samuel B.R., additional, Fekete, Eva M., additional, Brozoski, Daniel T., additional, Wackman, Kelsey K., additional, Burnett, Colin M.L., additional, Nakagawa, Pablo, additional, Sigmund, Curt D., additional, Segar, Jeffrey L., additional, and Grobe, Justin L., additional

Published
2023
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12. Genetic Ablation of Prorenin Receptor in The Rostral Ventrolateral Medulla Influences Blood Pressure And Hydromineral Balance in Deoxycorticosterone-Salt Hypertension

Author

Mathieu, Natalia M, primary, Fekete, Eva M, additional, Muskus, Patricia C, additional, Brozoski, Daniel T, additional, Lu, Ko-Ting, additional, Wackman, Kelsey K, additional, Gomez, Javier, additional, Fang, Shi, additional, Reho, John J, additional, Grobe, Connie C, additional, Vazirabad, Ibrahim, additional, Mouradian, Gary C, additional, Hodges, Matthew R, additional, Segar, Jeffrey L, additional, Grobe, Justin L, additional, Sigmund, Curt D, additional, and Nakagawa, Pablo, additional

Published
2023
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19. Cardiometabolic Consequences of Deleting the Regulator of G protein Signaling-2 ( Rgs2 ) From Cells Expressing Agouti-Related Peptide or the ANG (Angiotensin) II Type 1A Receptor in Mice

Author

Ritter, McKenzie L., primary, Deng, Guorui, additional, Reho, John J., additional, Deng, Yue, additional, Sapouckey, Sarah A., additional, Opichka, Megan A., additional, Balapattabi, Kirthikaa, additional, Wackman, Kelsey K., additional, Brozoski, Daniel T., additional, Lu, Ko-Ting, additional, Paradee, William J., additional, Gibson-Corley, Katherine N., additional, Cui, Huxing, additional, Nakagawa, Pablo, additional, Morselli, Lisa L., additional, Sigmund, Curt D., additional, and Grobe, Justin L., additional

Published
2022
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21. Chronic intracerebroventricular infusion of angiotensin II causes dose- and sex-dependent effects on intake behaviors and energy homeostasis in C57BL/6J mice

Author

Oliveira, Vanessa, primary, Reho, John J., additional, Balapattabi, Kirthikaa, additional, Ritter, McKenzie L., additional, Mathieu, Natalia M., additional, Opichka, Megan A., additional, Lu, Ko-Ting, additional, Grobe, Connie C., additional, Silva, Sebastião D., additional, Wackman, Kelsey K., additional, Nakagawa, Pablo, additional, Segar, Jeffrey L., additional, Sigmund, Curt D., additional, and Grobe, Justin L., additional

Published
2022
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25. Abstract P040: Angiotensin II Type 1 Receptor Is Expressed In Agouti-related Peptide Neurons Of The Hypothalamic Arcuate Nucleus Within Adult Human Brain

Author

Ritter, McKenzie L, primary, Balapattabi, Kirthikaa, additional, Lowman, Allison K, additional, Connelly, Jennifer M, additional, Coss, Dylan J, additional, LaViolette, Peter S, additional, Nakagawa, Pablo, additional, Sigmund, Curt D, additional, Morselli, Lisa L, additional, and Grobe, Justin L, additional

Published
2022
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28. Cardiometabolic effects of DOCA-salt in male C57BL/6J mice are variably dependent on sodium and nonsodium components of diet

Author

Patil, Chetan N., primary, Ritter, McKenzie L., additional, Wackman, Kelsey K., additional, Oliveira, Vanessa, additional, Balapattabi, Kirthikaa, additional, Grobe, Connie C., additional, Brozoski, Daniel T., additional, Reho, John J., additional, Nakagawa, Pablo, additional, Mouradian, Gary C., additional, Kriegel, Alison J., additional, Kwitek, Anne E., additional, Hodges, Matthew R., additional, Segar, Jeffrey L., additional, Sigmund, Curt D., additional, and Grobe, Justin L., additional

Published
2022
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29. Melanocortin MC4R receptor is required for energy expenditure but not blood pressure effects of angiotensin II within the mouse brain

Author

Oliveira, Vanessa, primary, Riedl, Ruth A., additional, Claflin, Kristin E., additional, Mathieu, Natalia M., additional, Ritter, McKenzie L., additional, Balapattabi, Kirthikaa, additional, Wackman, Kelsey K., additional, Reho, John J., additional, Brozoski, Daniel T., additional, Morgan, Donald A., additional, Cui, Huxing, additional, Rahmouni, Kamal, additional, Burnett, Colin M. L., additional, Nakagawa, Pablo, additional, Sigmund, Curt D., additional, Morselli, Lisa L., additional, and Grobe, Justin L., additional

Published
2022
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30. Deletion of Prorenin Receptor in the Rostral Ventrolateral Medulla Results in Biphasic and Sex‐Dependent Pressor Responses in Deoxycorticosterone Acetate‐salt Hypertension

Author

Nakagawa, Pablo, primary, Brozoski, Daniel, additional, Mathieu, Natalia M., additional, Lu, Ko‐Ting, additional, Gomez, Javier, additional, Reho, John, additional, Fang, Shi, additional, Segar, Jeffrey L., additional, Grobe, Justin L., additional, and Sigmund, Curt D., additional

Published
2022
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32. Methods for the Comprehensive in vivo Analysis of Energy Flux, Fluid Homeostasis, Blood Pressure, and Ventilatory Function in Rodents

Author

Reho, John J., primary, Nakagawa, Pablo, additional, Mouradian, Gary C., additional, Grobe, Connie C., additional, Saravia, Fatima L., additional, Burnett, Colin M. L., additional, Kwitek, Anne E., additional, Kirby, John R., additional, Segar, Jeffrey L., additional, Hodges, Matthew R., additional, Sigmund, Curt D., additional, and Grobe, Justin L., additional

Published
2022
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33. Cardiometabolic Consequences of Deleting the Regulator of G protein Signaling-2 ( ) From Cells Expressing Agouti-Related Peptide or the ANG (Angiotensin) II Type 1A Receptor in Mice.

Author

Ritter, McKenzie L., Deng, Guorui, Reho, John J., Deng, Yue, Sapouckey, Sarah A., Opichka, Megan A., Balapattabi, Kirthikaa, Wackman, Kelsey K., Brozoski, Daniel T., Lu, Ko-Ting, Paradee, William J., Gibson-Corley, Katherine N., Cui, Huxing, Nakagawa, Pablo, Morselli, Lisa L., Sigmund, Curt D., and Grobe, Justin L.

Abstract

Background: RGS (regulator of G protein signaling) family members catalyze the termination of G protein signaling cascades. Single nucleotide polymorphisms in the RGS2 gene in humans have been linked to hypertension, preeclampsia, and anxiety disorders. Mice deficient for Rgs2 (Rgs2Null) exhibit hypertension, anxiety, and altered adipose development and function.Methods: To study cell-specific functions of RGS2, a novel gene-targeted mouse harboring a conditional allele for the Rgs2 gene (Rgs2Flox) was developed. These mice were bred with mice expressing Cre-recombinase via the Agouti-related peptide locus (Agrp-Cre) to cause deletion of Rgs2 from all cells expressing Agrp (Rgs2Agrp-KO), or a novel transgenic mouse expressing Cre-recombinase via the ANG (angiotensin) type 1A receptor (Agtr1a/ AT1A) promoter encoded in a bacterial artificial chromosome (BAC-AT1A-Cre) to delete Rgs2 in all Agtr1a-expressing cells (Rgs2AT1A-KO).Results: Whereas Rgs2Flox, Rgs2Agrp-KO, and BAC-AT1A-Cre mice exhibited normal growth and survival, Rgs2AT1A-KO exhibited pre-weaning lethality. Relative to littermates, Rgs2Agrp-KO exhibited reduced fat gains when maintained on a high fat diet, associated with increased energy expenditure. Similarly, surviving adult Rgs2AT1A-KO mice also exhibited increased energy expenditure. Surprisingly, given the hypertensive phenotype previously reported for Rgs2Null mice and evidence supporting a role for RGS2 in terminating AT1A signaling in various cell types, Rgs2AT1A-KO mice exhibited normal blood pressure, ingestive behaviors, and renal functions, both before and after chronic infusion of ANG (490 ng/kg/min, sc).Conclusions: These results demonstrate the development of a novel mouse with conditional expression of Rgs2 and illustrate the role of Rgs2 within selected cell types for cardiometabolic control. [ABSTRACT FROM AUTHOR]

Published
2022
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34. Chronic intracerebroventricular infusion of angiotensin II causes dose- and sexdependent effects on intake behaviors and energy homeostasis in C57BL/6J mice.

Author

Oliveira, Vanessa, Reho, John J., Balapattabi, Kirthikaa, Ritter, McKenzie L., Mathieu, Natalia M., Opichka, Megan A., Ko-Ting Lu, Grobe, Connie C., Silva Jr, Sebastião D., Wackman, Kelsey K., Nakagawa, Pablo, Segar, Jeffrey L., Sigmund, Curt D., and Grobe, Justin L.

Subjects
ANGIOTENSIN II, LABORATORY mice, HOMEOSTASIS, RENIN-angiotensin system, FLUID control, DRINKING (Physiology), WATER-electrolyte balance (Physiology)
Abstract

The renin-angiotensin system (RAS) within the brain is implicated in the control of fluid and electrolyte balance, autonomic functions, blood pressure, and energy expenditure. Mouse models are increasingly used to explore these mechanisms; however, sex and dose dependencies of effects elicited by chronic intracerebroventricular (ICV) angiotensin II (ANG II) infusion have not been carefully established in this species. To examine the interactions among sex, body mass, and ICV ANG II on ingestive behaviors and energy balance, young adult C57BL/6J mice of both sexes were studied in a multiplexed metabolic phenotyping system (Promethion) during chronic infusion of ANG II (0, 5, 20, or 50 ng/h). At these infusion rates, ANG II caused accelerating dose-dependent increases in drinking and total energy expenditure in male mice, but female mice exhibited a complex biphasic response with maximum responses at 5 ng/h. Body mass differences did not account for sex-dependent differences in drinking behavior or total energy expenditure. In contrast, resting metabolic rate was similarly increased by ICV ANG II in a dose-dependent manner in both sexes after correction for body mass. We conclude that chronic ICV ANG II stimulates water intake, resting, and total energy expenditure in male C57BL/6J mice following straightforward accelerating dose-dependent kinetics, but female C57BL/6J mice exhibit complex biphasic responses to ICV ANG II. Furthermore, control of resting metabolic rate by ANG II is dissociable from mechanisms controlling fluid intake and total energy expenditure. Future studies of the sex dependency of ANG II within the brain of mice must be designed to carefully consider the biphasic responses that occur in females. [ABSTRACT FROM AUTHOR]

Published
2022
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40. Angiotensin-(1-7) upregulates cardiac nitric oxide synthase in spontaneously hypertensive rats

Author

Costa, Maria A., Verrilli, Maria A. Lopez, Gomez, Karina A., Nakagawa, Pablo, Pena, Clara, Arranz, Cristina, and Gironacci, Mariela M.

Subjects
Hypertension -- Risk factors, Hypertension -- Genetic aspects, Hypertension -- Care and treatment, Hypertension -- Research, Nitric oxide -- Physiological aspects, Nitric oxide -- Genetic aspects, Nitric oxide -- Research, Angiotensin -- Physiological aspects, Angiotensin -- Genetic aspects, Angiotensin -- Research, Biological sciences
Abstract

It has been shown that angiotensin (ANG)-(1-7) activates nitric oxide synthase (NOS) in isolated ventricular myocytes from normotensive rats. Since many ANG-(1-7) actions are enhanced in situations of increased ANG II activity, as in hypertension, in this study we investigated the in vivo effect of ANG-(1-7) on NOS activity and expression of endothelial (eNOS), neuronal (nNOS), and inducible NOS (iNOS) in ventricles from spontaneously hypertensive rats (SHR). Rats were subjected to a 60-min ANG-(1-7) infusion (0.35 nmol/min); controls received saline. NOS activity was measured using the NADPH diaphorase histochemical method and by the conversion of L-[[sup.14]C]arginine to citrulline, and NOS phosphorylation and expression were determined using Western blotting. In SHR, ANG-(1-7) infusion diminished mean arterial pressure from 180 [+ or -] 9 to 146 [+ or -] 9 mmHg (P < 0.05), and this effect was prevented by nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor. In addition, NOS activity and eNOS phosphorylation were increased by ANG-(1-7) infusion. Ventricular eNOS and nNOS expression were increased 67.4 [+ or -] 6.4 and 51 [+ or -] 10%, respectively, by ANG-(1-7), whereas iNOS was not changed. In another set of experiments, we evaluated the mechanism by which ANG-(1-7) modifies NOS activity. Isolated ventricle slices preincubated with ANG-(1-7) showed an increase in NOS activity and eNOS phosphorylation, which was blocked by an [AT.sub.2] and a bradykinin [B.sub.2] receptor antagonist, but not by the Mas receptor antagonist. Our results show that in rats in a hypertensive state, ANG-(1-7) infusion upregulates cardiac NOS expression and activity through an [AT.sub.2]- and bradykinin-dependent mechanism. In this way ANG-(1-7) may eficit its cardioprotective action and contribute to some of the counterregulatory [AT.sub.2] receptor effects that oppose the [AT.sub.1] receptor-mediated effects. receptors; hypertension; heart; bradykinin doi: 10.1152/ajpheart.00850.2009.

Published
2010

41. Melanocortin MC4R receptor is required for energy expenditure but not blood pressure effects of angiotensin II within the mouse brain.

Author

Oliveira, Vanessa, Ried, Ruth A., Claflin, Kristin E., Mathieu, Natalia M., Ritter, McKenzie L., Balapattabi, Kirthikaa, Wackman, Kelsey K., Reho, John J., Brozoski, Daniel T., Morgan, Donald A., Huxing Cui, Rahmouni, Kamal, Burnett, Colin M. L., Nakagawa, Pablo, Sigmund, Curt D., Morselli, Lisa L., and Grobe, Justin L.

Subjects
ANGIOTENSIN II, MELANOCORTIN receptors, HYPOTHALAMUS, BLOOD pressure, TRANSGENIC mice, PEPTIDES
Abstract

The brain renin-angiotensin system (RAS) is implicated in control of blood pressure (BP), fluid intake, and energy expenditure (EE). Angiotensin II (ANG II) within the arcuate nucleus of the hypothalamus contributes to control of resting metabolic rate (RMR) and thereby EE through its actions on Agouti-related peptide (AgRP) neurons, which also contribute to EE control by leptin. First, we determined that although leptin stimulates EE in control littermates, mice with transgenic activation of the brain RAS (sRA) exhibit increased EE and leptin has no additive effect to exaggerate EE in these mice. These findings led us to hypothesize that leptin and ANG II in the brain stimulate EE through a shared mechanism. Because AgRP signaling to the melanocortin MC4R receptor contributes to the metabolic effects of leptin, we performed a series of studies examining RMR, fluid intake, and BP responses to ANG II in mice rendered deficient for expression of MC4R via a transcriptional block (Mc4r-TB). These mice were resistant to stimulation of RMR in response to activation of the endogenous brain RAS via chronic deoxycorticosterone acetate (DOCA)-salt treatment, whereas fluid and electrolyte effects remained intact. These mice were also resistant to stimulation of RMR via acute intracerebroventricular (ICV) injection of ANG II, whereas BP responses to ICV ANG II remained intact. Collectively, these data demonstrate that the effects of ANG II within the brain to control RMR and EE are dependent on MC4R signaling, whereas fluid homeostasis and BP responses are independent of MC4R signaling. [ABSTRACT FROM AUTHOR]

Published
2022
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42. β-Arrestin–Biased Agonist Targeting the Brain AT 1 R (Angiotensin II Type 1 Receptor) Increases Aversion to Saline and Lowers Blood Pressure in Deoxycorticosterone Acetate–Salt Hypertension

Author

Zanaty, Mario, primary, Seara, Fernando A.C., additional, Nakagawa, Pablo, additional, Deng, Guorui, additional, Mathieu, Natalia M., additional, Balapattabi, Kirthikaa, additional, Karnik, Sadashiva S., additional, Grobe, Justin L., additional, and Sigmund, Curt D., additional

Published
2021
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46. Failure to vasodilate in response to salt loading blunts renal blood flow and causes salt-sensitive hypertension

Author

Wu, Jing, primary, Agbor, Larry N, additional, Fang, Shi, additional, Mukohda, Masashi, additional, Nair, Anand R, additional, Nakagawa, Pablo, additional, Sharma, Avika, additional, Morgan, Donald A, additional, Grobe, Justin L, additional, Rahmouni, Kamal, additional, Weiss, Robert M, additional, McCormick, James A, additional, and Sigmund, Curt D, additional

Published
2020
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