Increased renal Na-K-ATPase, NCC, and β-ENaC abundance in obese Zucker rats

2001 ◽  
Vol 281 (4) ◽  
pp. F639-F648 ◽  
Author(s):  
Crystal A. Bickel ◽  
Joseph G. Verbalis ◽  
Mark A. Knepper ◽  
Carolyn A. Ecelbarger
Keyword(s):  
Blood Pressure ◽  
Zucker Rats ◽  
Sodium Retention ◽  
Α Subunit ◽  
Sodium Transporters ◽  
Sodium Hydrogen ◽  
Obese Rats ◽  
Sodium Hydrogen Exchanger ◽  
Obese Zucker Rats ◽  
Epithelial Sodium Channel Enac

Renal sodium retention, as a result of increased abundance of sodium transporters, may play a role in the development and/or maintenance of the increased blood pressure in obesity. To address this hypothesis, we evaluated the relative abundances of renal sodium transporters in lean and obese Zucker rats at 2 and 4 mo of age by semiquantitative immunoblotting. Mean systolic blood pressure was higher in obese rats relative to lean at 3 mo, P < 0.02. Furthermore, circulating insulin levels were 6- or 13-fold higher in obese rats compared with lean at 2 or 4 mo of age, respectively. The abundances of the α1-subunit of Na-K-ATPase, the thiazide-sensitive Na-Cl cotransporter (NCC or TSC), and the β-subunit of the epithelial sodium channel (ENaC) were all significantly increased in the obese rats' kidneys. There were no differences for the sodium hydrogen exchanger (NHE3), the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2 or BSC1), the type II sodium-phosphate cotransporter (NaPi-2), or the α-subunit of ENaC. These selective increases could possibly increase sodium retention by the kidney and therefore could play a role in obesity-related hypertension.

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 Regulation of the renal thiazide-sensitive Na-Cl cotransporter, blood pressure, and natriuresis in obese Zucker rats treated with rosiglitazone

2005 ◽  
Vol 289 (2) ◽  
pp. F442-F450 ◽  
Author(s):  
Osman Khan ◽  
Shahla Riazi ◽  
Xinqun Hu ◽  
Jian Song ◽  
James B. Wade ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Control Diet ◽  
Zucker Rats ◽  
Receptor Subtype ◽  
Protein Abundance ◽  
Lean Control ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
Nacl Load

Previously, we showed an increase in protein abundance of the renal thiazide-sensitive Na-Cl cotransporter (NCC) in young, prediabetic, obese Zucker rats relative to lean age mates (Bickel CA, Verbalis JF, Knepper MA, and Ecelbarger CA. Am J Physiol Renal Physiol 281: F639–F648, 2001). To test whether this increase correlated with increased thiazide sensitivity (NCC activity) and blood pressure, and could be modified by insulin-sensitizing agents, we treated lean and obese Zucker rats (9 wk old) with either a control diet or this diet supplemented with 3 mg/kg body wt rosiglitazone (RGZ), a peroxisomal proliferator-activated receptor subtype γ agonist and potent insulin-sensitizing agent, for 12 wk ( n = 9/group). The rise in blood pressure, measured continuously by radiotelemetry, was significantly blunted in the RGZ-treated obese rats. Similarly, blood glucose and urinary albumin were markedly decreased in these rats. RGZ-treated rats whether lean or obese excreted a NaCl load faster but excreted less sodium in response to hydrochlorothiazide, applied as a novel in vivo measure of NCC activity. Obese rats had increased renal protein abundance and urinary excretion of NCC; however, this was not significantly reduced by RGZ (densitometry in cortex homogenate − %lean control): 100 ± 9, 93 ± 4, 124 ± 9, and 141 ± 14 for lean control, lean RGZ, obese control, and obese RGZ, respectively. Subcellular localization, as evaluated by confocal microscopy and immunoblotting following differential centrifugation, of NCC was not different between rat groups. Overall, RGZ reduced blood pressure and thiazide sensitivity; however, the mechanism(s) did not seem to involve a decrease in NCC protein abundance or cellular location. Decreased NCC activity may have contributed to the maintenance of normotension in RGZ-treated obese rats.

Aldosterone infusion with high-NaCl diet increases blood pressure in obese but not lean Zucker rats

2006 ◽  
Vol 291 (3) ◽  
pp. F597-F605 ◽  
Author(s):  
S. Riazi ◽  
Osman Khan ◽  
Xinqun Hu ◽  
Carolyn A. Ecelbarger
Keyword(s):  
Blood Pressure ◽  
Plasma Renin ◽  
Zucker Rats ◽  
Sodium Reabsorption ◽  
Plasma Sodium ◽  
Insulin Resistant ◽  
Arterial Blood ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
Pressure Natriuresis

Insulin-resistant, obese Zucker rats have blunted pressure natriuresis and are mildly hypertensive. This may involve inappropriate regulation of the renin-angiotensin-aldosterone system. To evaluate mechanisms underlying this defect, we employed the model of aldosterone escape. Male lean (L) and obese (O) Zucker rats were infused with aldosterone (2.8 μg/g body wt3/4) via osmotic minipump while being fed a 0.02% NaCl diet (LS). After 4 days, six rats of each type were switched to a high-NaCl (HS) diet (4%) for 4 additional days. Mean arterial blood pressure measured by radiotelemetry was significantly increased by the HS diet only in obese rats (final mean mmHg): 104 (LLS), 99 (LHS), 103 (OLS), and 115 (OHS). Obese rats had relatively increased renal cortical abundance of the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) and whole kidney α- and β-ENaC (epithelial sodium channel) relative to lean rats. However, band density for the thiazide-sensitive (Na-Cl) cotransporter (NCC) was similarly reduced by HS in lean and obese rats (∼50%). Obese rats had relatively reduced creatinine clearances and plasma renin activities, effects exacerbated by HS. Furthermore, HS resulted in a 129% increase in urinary nitrates plus nitrites excretion in lean rats and led to, in contrast, a 46% reduction in obese rats. Plasma sodium and potassium concentrations were increased by HS in obese but not lean rats. Thus we demonstrate an impaired response to aldosterone infusion in obese relative to lean Zucker rats. This impairment may involve increased sodium reabsorption via NKCC2 or ENaC, decreased glomerular filtration rate, and/or nitric oxide bioavailability.

scholarly journals High Na intake increases renal angiotensin II levels and reduces expression of the ACE2-AT2R-MasR axis in obese Zucker rats

2012 ◽  
Vol 303 (3) ◽  
pp. F412-F419 ◽  
Author(s):  
Preethi Samuel ◽  
Quaisar Ali ◽  
Rifat Sabuhi ◽  
Yonnie Wu ◽  
Tahir Hussain
Keyword(s):  
Sodium Intake ◽  
Zucker Rats ◽  
Kidney Cortex ◽  
Complex Nature ◽  
Ang Ii ◽  
Pronounced Increase ◽  
High Sodium ◽  
High Sodium Intake ◽  
Obese Rats ◽  
Obese Zucker Rats

High sodium intake is known to regulate the renal renin-angiotensin system (RAS) and is a risk factor for the pathogenesis of obesity-related hypertension. The complex nature of the RAS reveals that its various components may have opposing effects on natriuresis and blood pressure regulation. We hypothesized that high sodium intake differentially regulates and shifts a balance between opposing components of the renal RAS, namely, angiotensin-converting enzyme (ACE)-ANG II-type 1 ANG II receptor (AT1R) vs. AT2-ACE2-angiotensinogen (Ang) (1–7)-Mas receptor (MasR), in obesity. In the present study, we evaluated protein and/or mRNA expression of angiotensinogen, renin, AT1A/BR, ACE, AT2R, ACE2, and MasR in the kidney cortex following 2 wk of a 8% high-sodium (HS) diet in lean and obese Zucker rats. The expression data showed that the relative expression pattern of ACE and AT1BR increased, renin decreased, and ACE2, AT2R, and MasR remained unaltered in HS-fed lean rats. On the other hand, HS intake in obese rats caused an increase in the cortical expression of ACE, a decrease in ACE2, AT2R, and MasR, and no changes in renin and AT1R. The cortical levels of ANG II increased by threefold in obese rats on HS compared with obese rats on normal salt (NS), which was not different than in lean rats. The HS intake elevated mean arterial pressure in obese rats (27 mmHg) more than in lean rats (16 mmHg). This study suggests that HS intake causes a pronounced increase in ANG II levels and a reduction in the expression of the ACE2-AT2R-MasR axis in the kidney cortex of obese rats. We conclude that such changes may lead to the potentially unopposed function of AT1R, with its various cellular and physiological roles, including the contribution to the pathogenesis of obesity-related hypertension.

scholarly journals Plasma calcitonin gene-related peptide is increased prior to obesity, and sensory nerve desensitization by capsaicin improves oral glucose tolerance in obese Zucker rats

2005 ◽  
Vol 153 (6) ◽  
pp. 963-969 ◽  
Author(s):  
Dorte X Gram ◽  
Anker J Hansen ◽  
Michael Wilken ◽  
Torben Elm ◽  
Ove Svendsen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Tolerance ◽  
Sensory Nerve ◽  
Zucker Rats ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Nerve Activity ◽  
Calcitonin Gene ◽  
Obese Rats ◽  
Obese Zucker Rats

Objective: It has earlier been demonstrated that capsaicin-induced desensitization improves insulin sensitivity in normal rats. However, whether increased capsaicin-sensitive nerve activity precedes the onset of insulin resistance in diet-induced obesity – and therefore might be involved in the pathophysiology – is not known. Further, it is of relevance to investigate whether capsaicin desensitization improves glycaemic control even in obese individuals and we therefore chose the obese Zucker rats to test this. Design and methods: Plasma levels of calcitonin gene-related peptide (CGRP; a marker of sensory nerve activity) was assessed in 8-week-old Zucker rats. To investigate whether capsaicin desensitization (100 mg/kg at 9 weeks of age) would also ameliorate glycaemia in this non-diabetic model, we assessed oral glucose tolerance at 7 weeks after capsaicin. Results: It was found that plasma CGRP levels were elevated in obese Zucker rats prior to the onset of obesity (16.1±3.4 pmol/l in pre-obese Zucker rats vs 6.9±1.1 pmol/l in lean littermates; P = 0.015) despite similar body weights. Furthermore, capsaicin desensitization reduced both fasting blood glucose (4.3±0.2 mmol/l vs 5.1±0.2 mmol/l in controls; P = 0.050) as well as the mean blood glucose level during an oral glucose tolerance test (OGTT) (6.8±0.3 mmol/l vs 8.6±0.5 mmol/l in control obese rats; P = 0.024) whereas the plasma insulin levels during the OGTT were unchanged. However this did not lead to an improvement in insulin resistance or to a reduction of tissue triglyceride accumulation in muscle or liver. Conclusion: We concluded that capsaicin-induced sensory nerve desensitization improves glucose tolerance in Zucker rats. Since, in this study, plasma CGRP levels, a marker of sensory nerve activity, were increased in the pre-obese rats, our data support the hypothesis that increased activity of sensory nerves precedes the development of obesity and insulin resistance in Zucker rats.

scholarly journals Adipose-tissue-specific increase in glyceraldehyde-3-phosphate dehydrogenase activity and mRNA amounts in suckling pre-obese Zucker rats. Effect of weaning

1988 ◽  
Vol 254 (2) ◽  
pp. 483-487 ◽  
Author(s):  
I Dugail ◽  
A Quignard-Boulange ◽  
R Bazin ◽  
X Le Liepvre ◽  
M Lavau
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Zucker Rats ◽  
Tissue Specific ◽  
Gapdh Gene ◽  
Gapdh Activity ◽  
Weanling Rats ◽  
Obese Rats ◽  
Specific Increase ◽  
Obese Zucker Rats

The regulation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene expression was studied during the onset of obesity in the genetically obese (fa/fa) rat by determination of GAPDH activity and hybridizable mRNA amounts in adipose tissue and liver from suckling and weanling rats. GADPH activity remained low throughout the suckling period, and a burst of activity occurred after weaning in both lean and obese pups. As early as 7 days of age, adipose tissue from pre-obese rats displayed a significant increase in enzyme activity, whereas no difference could be detected in the liver. In both suckling (16 days of age) and weanling (30 days of age) obese rats a proportionate increase in GAPDH activity and mRNA amounts was observed in adipose tissue, but not in liver. It is concluded that the obese genotype influences GAPDH gene expression at a pretranslational level and in a tissue-specific manner. This phenomenon could partly contribute to the hyperactive fat accretion in the obese rat, since glycolysis is the major metabolic pathway for lipogenic substrates in adipose tissue.

Abstract P038: Testosterone Supplements Have Differential Effects on Blood Pressure in Old and Young Male Spontaneously Hypertensive Rats

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Rodrigo O Maranon ◽  
Licy L Yanes Cardozo ◽  
Carolina Dalmasso ◽  
Chetan N Patil ◽  
Andrew Harris ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Spontaneously Hypertensive Rats ◽  
Young Male ◽  
Zucker Rats ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Young Males ◽  
The Metabolic Syndrome ◽  
Younger Men ◽  
Obese Zucker Rats

Testosterone (“T”) supplements are widely used by men to improve their quality of life, libido, and protect against osteoporosis. In clinical studies, both high and low “T” levels were found to be associated with hypertension and cardiovascular risk. Endogenous “T” levels are reduced in obese men and rats. We have shown previously that “T” supplements in middle-aged (6 mos) obese Zucker rats improved symptoms of the metabolic syndrome and caused weight loss, but increased their blood pressure. How “T” supplements affect hypertensive men and rats is unknown. We hypothesized that “T” supplements would further increase blood pressure (BP) in both old and young male spontaneously hypertensive rats (SHR). Old (O=20-22 mos) and young (Y=10 wks) male SHR were treated with “T” (testosterone propionate 8 mg/10 mm silastic pellet; OT and YT, implanted sc) or placebo (empty pellets; OP and YP, sc). Pellets were changed every 3 weeks for 8 weeks. Mean arterial pressure (MAP) was measured by telemetry for 2 weeks. MAP in OP was higher than in YP (OP: 166±7 vs YP: 148±0.5 mmHg, p<0.001). As we predicted, “T” increased MAP in YT (YP: 148±1 vs YT: 157±1 mmHg, p<0.001). In contrast, “T” decreased MAP in OT (OP: 166±1 vs OT: 155±1 mmHg, p<0.001). These data suggest that in younger men, especially men who are already hypertensive, blood pressure should be monitored closely during “T” supplementation in order to prevent further cardiovascular disease. Since “T” reduced MAP in older male SHR, these data suggest that “T” supplements may not be as detrimental in older hypertensive men as in young men. Future studies will need to be done to determine the mechanisms by which “T” increases BP in young males and the mechanisms by which “T” reduces BP in old males. Supported by NIH-R01HL66072, PO1HL51971 (JFR), 14POST18640015 (ROM), EFF Endocrine Res Grant (LLY).

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

Increased renal α-ENaC and NCC abundance and elevated blood pressure are independent of hyperaldosteronism in vasopressin escape

2006 ◽  
Vol 291 (1) ◽  
pp. F49-F57 ◽  
Author(s):  
Swasti Tiwari ◽  
Randall K. Packer ◽  
Xinqun Hu ◽  
Yoshihisa Sugimura ◽  
Joseph G. Verbalis ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Urine Volume ◽  
Sprague Dawley ◽  
Α Subunit ◽  
Water Load ◽  
Arterial Blood ◽  
Sprague Dawley Rats ◽  
Solid Diet ◽  
Epithelial Sodium Channel Enac

Previously, we demonstrated that rats undergoing vasopressin escape had increased mean arterial blood pressure (MAP), plasma and urine aldosterone, and increased renal protein abundance of the α-subunit of the epithelial sodium channel (ENaC), the thiazide-sensitive Na-Cl cotransporter (NCC), and the 70-kDa band of γ-ENaC (Song J, Hu X, Khan O, Tian Y, Verbalis JG, and Ecelbarger CA. Am J Physiol Renal Physiol 287: F1076–F1083, 2004; Ecelbarger CA, Knepper MA, and Verbalis JG. J Am Soc Nephrol 12: 207–217, 2001). Here, we determine whether changes in these renal proteins and MAP require elevated aldosterone levels. We performed adrenalectomies (ADX) or sham surgeries on male Sprague-Dawley rats. Corticosterone and aldosterone were replaced to clamp these hormone levels. MAP was monitored by radiotelemetry. Rats were infused with 1-deamino-[8-d-arginine]-vasopressin (dDAVP) via osmotic minipumps (5 ng/h). At day 3 of dDAVP infusion, seven rats in each group were offered a liquid diet [water load (WL)] or continued on a solid diet (SD). Plasma aldosterone and corticosterone and urine aldosterone were increased by WL in sham rats. ADX-WL rats escaped, as assessed by early natriuresis followed by diuresis; however, urine volume and natriuresis were somewhat blunted. WL did not reduce the abundance or activity of 11-β-hydroxsteroid dehydrogenase type 2. Furthermore, the previously observed increase in renal aldosterone-sensitive proteins and escape-associated increased MAP persisted in clamped rats. The densitometry of immunoblots for NCC, α- and γ-70 kDa ENaC, respectively, were (% sham-SD): sham-WL, 159, 278, 233; ADX-SD, 69, 212, 171; ADX-WL, 116, 302, 161. However, clamping corticosteroids blunted the rise at least for NCC and γ-ENaC (70 kDa). Overall, the increase in aldosterone observed in vasopressin escape is not necessary for the increased expression of NCC, α- or γ-ENaC or increased MAP associated with “escape.”

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