scholarly journals Reduction of renal dopamine receptor expression in obese Zucker rats: role of sex and angiotensin II

2010 ◽  
Vol 299 (5) ◽  
pp. F1164-F1170 ◽  
Author(s):  
Xiaoyan Wang ◽  
Fengmin Li ◽  
Pedro A. Jose ◽  
Carolyn M. Ecelbarger
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Receptor Expression ◽  
Female Rats ◽  
Male Rats ◽  
Zucker Rats ◽  
Protein Levels ◽  
Obese Rats ◽  
Obese Zucker Rats

Dopamine produced by renal proximal tubules increases sodium excretion via a decrease in renal sodium reabsorption. Dopamine natriuresis is impaired in obese Zucker rats; however, the mechanism is not fully understood. To test the hypothesis that renal expression of one or more of the subtypes are altered in these rats, we measured whole kidney protein levels by immunoblotting of D1-like (D1R and D5R) and D2-like (D2R, D3R, and D4R) dopamine receptors in both male and female obese and lean Zucker rats. In obese males on 1% NaCl diet, D1R, D2R, D4R, and D5R were decreased, while D3R was increased, relative to lean rats. Under a 4% NaCl diet, D2R and D3R levels in obese rats were restored to lean levels. 4% NaCl diet reduced D5R in both body types, relative to 1% NaCl diet. Female rats had higher expression of D1R and D3R than did male; however, the sex difference for D1R was markedly blunted in obese rats. In obese rats, dietary candesartan (angiotensin II type 1 receptor blocker) normalized downregulated D1R and D2R, but either decreased (D3R), did not affect (D4R), or further downregulated (D5R) the other subtypes. Candesartan also decreased D4R in lean rats. In summary, reduced renal protein levels of D1R, D2R, D4R, and D5R in obese Zucker rats could induce salt sensitivity and elevate blood pressure. Increased angiotensin II type 1 receptor activity may be mechanistically involved in the decreased expression of D1R and D2R in obese rats. Finally, reduced D1R and D3R in male rats may contribute to sex differences in blood pressure.

scholarly journals Obese Zucker Rats Have Reduced Mineralocorticoid Receptor and 11β-Hydroxysteroid Dehydrogenase Type 1 Expression in Hippocampus—Implications for Dysregulation of the Hypothalamic-Pituitary-Adrenal Axis in Obesity

Endocrinology ◽  
2003 ◽  
Vol 144 (7) ◽  
pp. 2997-3003 ◽  
Author(s):  
Cecilia Mattsson ◽  
Maggie Lai ◽  
June Noble ◽  
Eoin McKinney ◽  
Joyce L. Yau ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Glucocorticoid Receptors ◽  
Hydroxysteroid Dehydrogenase ◽  
Male Rats ◽  
Zucker Rats ◽  
Mrna Levels ◽  
Hypothalamic Pituitary Adrenal ◽  
Obese Rats ◽  
Obese Zucker Rats

Abstract Obese Zucker rats have elevated basal corticosterone levels and an increased stress response suggestive of an increased activity of the hypothalamic-pituitary-adrenal (HPA) axis. We hypothesized that altered central expression of glucocorticoid receptors (GR), mineralocorticoid receptors (MR), and/or 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) contribute to these changes. In brains from young adult male rats, in situ hybridization and Western blotting showed that obese rats had normal hippocampal GR mRNA and protein levels. In contrast, in obese rats, 11βHSD1 mRNA levels were reduced in a subpopulation of hippocampal cells in the main neuronal layers (by 37–47%, P < 0.05), whereas 11βHSD1 levels in sparse high-expressing cells did not differ. MR mRNA was decreased in all regions of the hippocampus (by 37–49%, P < 0.05 for CA1–2 and P < 0.01 for dentate gyrus) and in frontal cortex (by 16%, P < 0.05) in obese rats. In whole hippocampal homogenates, however, neither the protein concentration of MR by Western blot nor activity of 11βHSD1 was measurably different between the phenotypes. To test the functional importance of lower central MR expression, groups of lean and obese rats were given spironolactone before restraint stress. In vehicle-treated animals, obese rats had higher plasma corticosterone levels than lean rats after stress (by ANOVA, P < 0.05). Spironolactone markedly increased the corticosterone response in both groups, but the incremental rise was smaller in the obese rats, so that spironolactone abolished the differences between groups. We conclude that lower levels of MR, but not GR, contribute to the increased HPA activity in the obese Zucker rats and that this seems more influential during stress than in the basal state. This may be exacerbated by impaired local regeneration of corticosterone by 11βHSD1. These abnormalities could contribute to the subtle changes in the HPA axis in rodent and human obesity.

scholarly journals Blood pressure response to angiotensin II is enhanced in obese Zucker rats and is attributed to an aldosterone-dependent mechanism

2012 ◽  
Vol 166 (8) ◽  
pp. 2417-2429 ◽  
Author(s):  
Helge Müller-Fielitz ◽  
Margot Lau ◽  
Olaf Jöhren ◽  
Florian Stellmacher ◽  
Markus Schwaninger ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Blood Pressure Response ◽  
Pressure Response ◽  
Zucker Rats ◽  
Obese Zucker Rats ◽  
Dependent Mechanism

scholarly journals Effects of Prehypertensive Losartan Treatment on Resistance Vessel Remodeling and Angiotensin II Type 1 Receptor Expression in Spontaneously Hypertensive Rats

2020 ◽  
Vol 33 (5) ◽  
pp. 471-471
Author(s):  
Ting-jun Wang ◽  
Wan-ru Chen ◽  
Xu Lin ◽  
Gui-li Lian ◽  
Chang-sheng Xu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Receptor Expression ◽  
Mesenteric Arteries ◽  
Resistance Vessel ◽  
Spontaneously Hypertensive ◽  
Vessel Remodeling ◽  
Wistar Kyoto ◽  
Losartan Treatment

Abstract Background To study the effects of prehypertensive losartan treatment on blood pressure, resistance vessel remodeling, and angiotensin II type 1 receptor (AT1R) expression in adult spontaneously hypertensive rats (SHRs). Methods Four-week-old SHR and Wistar-Kyoto rats were randomly divided into losartan-treated and untreated groups. Losartan was administrated by gavage from 4 to 10 weeks old. Blood pressure was monitored by the tail-cuff method till 26 weeks old. The third grade mesenteric arteries were then isolated. Vessel structure, relaxation reactivity, angiotensin II type 1 receptor expression, and angiotensin II levels were analyzed. Results Losartan treatment from 4 to 10 weeks of age significantly lowered systolic blood pressure from 10 to 26 weeks in SHR. At 26 weeks old, wall thickness to lumen radius and wall area to lumen area of mesenteric arteries were significantly lower in losartan-treated than untreated SHR (P < 0.01). Maximum relaxation to acetylcholine and its pD2 were increased in losartan-treated compared to untreated SHR (P < 0.01). Angiotensin II type 1 receptor mRNA and protein levels were significantly reduced in losartan-treated SHR (P < 0.01). However, angiotensin II levels in plasma and mesenteric arteries of losartan-treated SHR were higher than those of untreated SHR (P < 0.05). Losartan treatment lowered systolic blood pressure in Wistar-Kyoto at the age of 10 weeks (P < 0.05), but had no significant effect on blood pressure after 14 weeks or mesenteric arteries at 26 weeks. Conclusions Blood pressure reduction induced by prehypertensive losartan treatment ameliorates resistance vessel remodeling and downregulates angiotensin II type 1 receptor expression in adult SHR.

Abstract P231: Offspring of Captopril Treated Spontaneously Hypertensive Rats Have Lower Angiotensin II Type 1 Receptor Expression Which is Associated With Lower Blood Pressure

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
J X Masjoan-Juncos ◽  
Tang-Dong Liao ◽  
Ginette Bordcoch ◽  
Cesar A Romero ◽  
Oscar A Carretero
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Posterior Wall ◽  
Receptor Expression ◽  
Shr Rats ◽  
Spontaneously Hypertensive ◽  
Intracerebroventricular Infusion ◽  
Lower Blood ◽  
The Brain

It has been reported that SHR rats receiving angiotensin converting enzyme (ACE) inhibitor Captopril decrease blood pressure (BP) in at least two generation after the treatment was stopped. A decreased response to an intracerebroventricular infusion angiotensin I and angiotensin II in treated animals and their offspring was reported; however there is no reported mechanism that explains the changes observed in the untreated offspring of the Captopril treated animals. We hypothesize that captopril reduces angiotensin II type 1 receptor (AT1R) expression in CNS of the offspring of SHR rats treated with captopril. Animal groups are as follows: control animals, captopril treated animals, offspring of the control animals, offspring of the treated animals where the mother was removed from the treatment immediately after giving birth and Offspring of treated animals where the mother was removed from the treatment at weaning. BP was measured by intra-arterial method and Tail cuff. AT1R expression was measured in brain tissue using the posterior wall of the forth ventricle, as well as the top half of the brain stem. BP was different between treated groups and their offspring vs. control (Table 1). AT1R expression was significantly reduced in both offspring groups of the treated animals, when compared to control (Table 1). Therefore we conclude that captopril reduces blood pressure in the offspring of captopril treated SHR rats and that associates with a decrease in AT1R expression in CNS. Further research is necessary to determine the possible epigenetic mechanisms involved in AT1R reduction.

scholarly journals Endocrine, metabolic and cardioprotective effects of hexarelin in obese Zucker rats

2000 ◽  
Vol 166 (3) ◽  
pp. 529-536 ◽  
Author(s):  
V De Gennaro-Colonna ◽  
G Rossoni ◽  
D Cocchi ◽  
AE Rigamonti ◽  
F Berti ◽  
...  
Keyword(s):  
Chronic Treatment ◽  
Plasma Cholesterol ◽  
Left Ventricular ◽  
Male Rats ◽  
Zucker Rats ◽  
Coronary Perfusion ◽  
Mrna Levels ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
Plasma Gh

Genetically obese male Zucker rats have an impaired secretion of GH, coupled to hyperinsulinemia, hyperlipidemia and glucose intolerance. The aim of this study was to evaluate whether a chronic treatment with hexarelin, a synthetic enkephalin-derived hexapeptide with a potent GH-releasing activity, might be able to ameliorate the somatotropic function and reverse some metabolic alterations associated with obesity in male obese Zucker rats. Furthermore, as decreased GH secretion and insulin resistance are associated with increased cardiovascular risk, we also tested the capacity of hexarelin to prevent postischemic ventricular dysfunction in hearts of male obese Zucker rats. Obese and lean male rats of the Zucker strain were treated with hexarelin (80 microgram/kg, b.i.d., s.c.) or saline (1 ml/kg, b.i.d., s.c.) for 30 days. An acute hexarelin injection (80 microgram, s.c.) at the 28th day of treatment elicited a rise in plasma GH levels in ! lean but not in obese rats (pretreated or not with hexarelin); lean rats chronically treated with hexarelin showed a greater increase in plasma GH as compared with control counterparts. At the end of the experiment, pituitary GH mRNA levels were significantly reduced in obese rats and hexarelin administration failed to increase pituitary GH mRNA and IGF-I concentrations in plasma and heart. Chronic treatment with hexarelin increased insulinemia and blood glucose levels in obese but not in lean rats, left unaltered the high triglyceride levels but significantly decreased plasma cholesterol concentrations in obese rats. Heart preparations from lean and obese Zucker rats treated with saline, subjected to low flow ischemia and reperfusion, showed at reperfusion: a) a low recovery of postischemic left ventricular developed pressure (LVDP), coupled to a substantial increase in coronary perfusion pressure, and b) a marked increase in creatine kinase released in the perfusates. Hexare! lin administration for 30 days counteracted the heart ischemic damage both in lean and obese Zucker rats. In fact, the recovery of LVDP at reperfusion was significantly higher than in controls and the increase in coronary resistance was minimal. Collectively, these data indicate that a 30-day treatment with hexarelin was unable to improve somatotropic function in male obese Zucker rats but was successful in decreasing plasma cholesterol concentrations. Hexarelin exerted a cardioprotective effect in both lean and obese rats. The heart-protective activity afforded by the peptide was divorced from any stimulation of the GH axis and is probably exerted through activation of specific cardiac receptors.

scholarly journals Mechanisms of dysregulation of 11 beta-hydroxysteroid dehydrogenase type 1 in obese Zucker rats

2000 ◽  
Vol 167 (3) ◽  
pp. 533-539 ◽  
Author(s):  
DE Livingstone ◽  
CJ Kenyon ◽  
BR Walker
Keyword(s):  
Weight Gain ◽  
Hydroxysteroid Dehydrogenase ◽  
Zucker Rats ◽  
Tissue Specific ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
The Difference ◽  
Underlying Mechanisms ◽  
Omental Fat

Obesity has been associated with alterations in glucocorticoid metabolism in both man and rodents, but the underlying mechanisms remain undefined. We have previously reported tissue-specific alterations in 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) in obese Zucker rats predicting that reactivation of corticosterone is decreased in liver but increased in omental fat. The mechanisms of dysregulation of 11 beta-HSD1 in obesity are not known, and in this study we have investigated the potential role of glucocorticoids and insulin. In one experiment lean and obese Zucker rats were adrenalectomised, and in a second experiment they were sensitised to insulin by treatment with either metformin or rosiglitazone. Adrenalectomy (ADX) of obese animals attenuated weight gain, normalised hepatic 11 beta-HSD1 kinetics by an effect on V(max) (V(max)in sham-operated animals, 6.6+/-1.1 nmol/min per mg in lean vs 3.4+/-0.6 in obese, P<0.01; in ADX animals 5.9+/-1.1 in lean vs 6.9+/-1.8 in obese, NS), and reversed the difference in omental fat 11 beta-HSD1 activity (18.9+/-4.2% in lean ADX vs 8.2+/-2.3 in obese ADX, P=0.03). Both metformin and rosiglitazone improved insulin sensitivity in obese, but not lean animals, and had no effect on 11 beta-HSD1 activity in either liver or fat. However, both treatments normalised adrenal hypertrophy in obese animals (48+/-29 mg in obese vehicle vs 37+/-1.2 in metformin and 38+/-1.8 in rosiglitazone treated, both P<0.01), and rosiglitazone tended to attenuate hypercorticosteronaemia in obese rats. Neither treatment attenuated weight gain; in fact, weight gain was enhanced by rosiglitazone in obese rats. In summary, altered 11 beta-HSD1 activity in obese Zucker rats is reversible following adrenalectomy, but the mechanism is unclear since adrenalectomy also normalises many other metabolic abnormalities. The current study suggests that hyperinsulinaemia is not responsible for tissue-specific dysregulation of 11 beta-HSD1. However, insulin sensitisation did reverse adrenal hypertrophy, suggesting that hyperinsulinaemia may be a key factor contributing to activation of the hypothalamic- pituitary-adrenal (HPA) axis in obesity independently of tissue-specific changes in 11 beta-HSD1.

scholarly journals Impact of Mineralocorticoid Receptor And Angiotensin Ii Type 1 Receptor Antagonism on Blood Pressure Regulation in Obese Zucker Rats: Role of Sex Differences

2020 ◽  
Author(s):  
Jussara M do Carmo ◽  
Alexandre A da Silva ◽  
John E Hall
Keyword(s):  
Blood Pressure ◽  
Sex Differences ◽  
Mineralocorticoid Receptor ◽  
Combined Treatment ◽  
Zucker Rats ◽  
Male And Female ◽  
Obese Zucker Rats ◽  
Males And Females

Abstract Background Previous studies suggest that obesity-induced hypertension in females, but not males, is due to leptin-mediated stimulation of aldosterone secretion and subsequent activation of the mineralocorticoid receptor (MR). Although angiotensin II type 1 receptor (AT1R) antagonism lowers blood pressure (BP) in male obese Zucker rats (OZR), which have defective leptin signaling, the potential role of sex differences in BP responses to RAAS blockade, including MR antagonism, in obesity is still unclear. We tested the cardiovascular effects of MR antagonism, alone or in combination with AT1R blockade in male and female OZR (n=5/sex) and lean Zucker rats (LZR, n=7/sex). Methods BP and heart rate (HR) were measured by telemetry 24-hrs/day. After a 6-day control period, spironolactone (40 mg/kg/day) was given for 10 days followed by a 7-day combined treatment with losartan (20 mg/kg/day), and followed by 6-day post-treatment recovery period. Results Compared to lean rats, OZR were hypertensive (Mean arterial pressure: 115±4 vs. 104±2 and 111±s vs. 100±3 mmHg for males and females) and had lower HR (355±9 vs. 393±7 and 367±10 vs. 412±13 bpm). MR blockade alone did not alter BP or HR in lean or obese male and female Zucker rats, whereas combined treatment reduced BP in obese and lean rats by 31±3 vs. 21±1 and 8±1 vs. 5±1 mmHg in males and females, respectively. No changes were observed in HR. Conclusions These results suggest that there are important sex differences in BP responses to chronic AT1R blockade but no major involvement of MR activation in BP regulation in OZR.

Expression of dopaminergic receptors in the hypothalamus of lean and obese Zucker rats and food intake

2002 ◽  
Vol 283 (4) ◽  
pp. R905-R910 ◽  
Author(s):  
Sergueï O. Fetissov ◽  
Michael M. Meguid ◽  
Tomoi Sato ◽  
Li-Hua Zhang
Keyword(s):  
Food Intake ◽  
Dopamine Release ◽  
Behavioral Sensitization ◽  
Receptor Expression ◽  
Zucker Rats ◽  
Dopaminergic Receptors ◽  
Hypothalamic Area ◽  
Receptor Mrna ◽  
Obese Rats ◽  
Obese Zucker Rats

As revealed by previous microdialysis studies, basal and food intake-accompanied dopamine release significantly differs in the hypothalamus of obese vs. lean Zucker rats. In the present study, we determined whether dopaminergic receptors are also compromised in obesity. Dopaminergic D1and D2 receptor mRNA expression was studied in the ventromedial hypothalamus (VMH), lateral hypothalamic area (LHA), and the adenohypophysis (AH) of obese and lean Zucker rats using RT-PCR technique. In obese Zucker rats, we found an upregulation of D1 receptor mRNA in the VMH and AH and a downregulation in the LHA, whereas D2 receptor mRNA was downregulated in both the VMH and LHA, but not changed in the AH, compared with lean rats. Also, an increase of D1 receptor staining was seen in the paraventricular nucleus of obese rats by immunohistochemistry. We selected the VMH to test if the observed changes in the dopamine receptor expression of obese rats induce behavioral sensitization to dopamine as expressed by hyperphagia. The overnight food-deprived rats received a single VMH injection (10 nmol) of sulpiride (D2receptor antagonist) or saline as control, then food was provided and 1-h food intake was measured. Food intake after sulpiride vs. saline injection was greater in obese rats but was not different in lean rats. Our data suggest that downregulation of D2 receptor in the hypothalamus at least in the VMH induces behavior sensitization for having large meals. Low D2 receptor expression may be causal for an exaggerated dopamine release observed in obese rats during food ingestion and for reduced satiety feedback effect of dopamine. High level of D1 receptor expression in the VMH and low in the LHA may also contribute to the specific feeding pattern in obese rats represented by large meal size and low meal number.

Responsiveness of isolated adrenocortical cells from lean and obese Zucker rats to ACTH

1988 ◽  
Vol 255 (3) ◽  
pp. E229-E235
Author(s):  
B. D. White ◽  
W. D. Davenport ◽  
J. R. Porter
Keyword(s):  
Plasma Corticosterone ◽  
Zona Glomerulosa ◽  
Female Rats ◽  
Zucker Rats ◽  
Response Curves ◽  
Adrenocortical Cells ◽  
Serum Corticosterone ◽  
Obese Rats ◽  
Corticosterone Response ◽  
Obese Zucker Rats

Morning plasma corticosterone concentrations have been reported to be elevated in obese Zucker rats compared with lean rats. The aim of this study was to determine if differences in adrenal sensitivity or maximal responsiveness to adrenocorticotropic hormone (ACTH)-(1-24) could account for this disparity. Serum and adrenal glands were collected from lean and obese, male and female Zucker rats (10-13 wk old) between 10:00 and 11:00 A.M. Adrenocortical cells were isolated and challenged with ACTH-(1-24). The serum corticosterone and ACTH concentrations were significantly greater in obese males compared with lean males (45.3 +/- 10.3 vs. 23.2 +/- 1.45 ng/ml and 156.6 +/- 15.3 vs. 113.3 +/- 9.4 pg/ml, respectively). Although serum corticosterone concentrations were similar in female rats, serum ACTH concentrations tended (P = 0.07) to be lower in obese female rats than in lean female rats (67.6 +/- 9.3 vs. 103.5 +/- 15.1 pg/ml, respectively). The median effective concentration (EC50) and the maximal corticosterone response per microgram of DNA of dose-response curves derived from lean and obese rats were not significantly different. Additionally, a morphometric evaluation of adrenal tissue from lean and obese rats suggested that cells of the zona glomerulosa were smaller in obese rats than in lean rats. Our data confirm that morning serum corticosterone concentrations are elevated in 10- to 13-wk-old male Zucker rats. This difference does not appear to be due to differences in the sensitivity or maximal secreting capacity of adrenocortical cells to ACTH.

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