Development Of Obesity-induced Hypertension Research Articles

Selective Afferent Denervation in Epididymal White Adipose Tissue Reduces Blood Pressure in Obese Male Mice Exposed to Early Life Stress

Visceral adiposity has been largely implicated in increased sympathetic activation, and pathogenesis and target organ damage associated with the development of obesity-induced hypertension. The experimental stimulation of afferent excitatory signals from adipose tissue has been shown to contribute with the increased sympathetic activation associated with obesity-induced hypertension as part of a sympathoexcitatory mechanism called the adipose afferent reflex (AAR). Previous studies from our lab have shown that male mice exposed to maternal separation and early weaning (MSEW), a mouse model of early life stress, display increased mean arterial pressure (MAP) compared to control mice when fed a high fat diet (HF) that correlates with increased neuronal activation in non-endocrine neurons in the posterior paraventricular nucleus of the hypothalamus. Moreover, MSEW-HF males display exacerbated blood pressure responses to the acute stimulation of the AAR in epididymal white adipose tissue (eWAT) compared to controls. Therefore, the aim of this study was to determine the contribution of the afferent sensory nerves innervating the eWAT in the chronically increased blood pressure displayed by obese MSEW male mice. Male C57BL/6J mice pups were separated from the dams from postnatal day (PD) 2 to PD 16 and weaned early on PD 17. Control litters remained undisturbed with the dams and were weaned on PD 21. After weaning, Control and MSEW mice were placed on HF (60% Kcal from fat) for four months. At 14 weeks, mice (n=8) were implanted with radiotelemetry for chronic MAP measurements. After two weeks of recovery, MAP baseline was recorded during five consecutive days followed by eWAT denervation. For this procedure, eWAT was exposed and infused with vehicle (0.6% ethanol in saline; 4ul; 8 sites; bilateral) or resiniferatoxin (RTX, 10 pmol/ul, 8 sites, 4ul; bilateral). Then, MAP was continuously recorded for 4 days. RTX procedure in eWAT was validated using a GFP reporter mouse for sensory neurons, B6.129P2(Cg)-Calcatm1.1(EGFP/HBEGF)Mjz/Mmnc, and the absence of a green signal in the RTX-treated areas confirmed the afferent denervation. Sympathetic index was evaluated before and after denervations by a single injection of a ganglion blocker (mecamylamine; 5mg/kg; ip). MSEW mice fed a HF displayed significantly increased baseline MAP compared to controls (120±2 vs. 110±2 mmHg respectively, p<0.05). Ganglion blockade induced a greater MAP reduction in MSEW compared to controls (Delta MAP: -20±2 vs. -12±2 mmHg, respectively, p<0.05). Sham denervation did not change MAP from baseline in both groups. However, RTX denervation only decrease MAP in MSEW-HF mice (baseline: 120±2 vs. RTX: 112±2 mmHg, p<0.05) and abolished the baseline MAP differences between groups. MAP decrease in response to ganglion blockade after RTX denervation was similar in both groups (MSEW: -14±4 vs. Control: -15±2 mmHg). Taken together these results show that afferent sensory nerves from epididymal white adipose tissue contribute to the exacerbated obesity-induced hypertension in male mice exposed to early life stress.

Sensory signals mediating high blood pressure via sympathetic activation: role of adipose afferent reflex

Blood pressure regulation in health and disease involves a balance between afferent and efferent signals from multiple organs and tissues. Although there are numerous reviews focused on the role of sympathetic nerves in different models of hypertension, few have revised the contribution of afferent nerves innervating adipose tissue and their role in the development of obesity-induced hypertension. Both clinical and basic research support the beneficial effects of bilateral renal denervation in lowering blood pressure. However, recent studies revealed that afferent signals from adipose tissue, in an adipose-brain-peripheral pathway, could contribute to the increased sympathetic activation and blood pressure during obesity. This review focuses on the role of adipose tissue afferent reflexes and briefly describes a number of other afferent reflexes modulating blood pressure. A comprehensive understanding of how multiple afferent reflexes contribute to the pathophysiology of essential and/or obesity-induced hypertension may provide significant insights into improving antihypertensive therapeutic approaches.

Role of cannabinoid receptor type 1 in rostral ventrolateral medulla in high-fat diet-induced hypertension in rats.

Stimulation of cannabinoid type 1 (CB1) receptor in the rostral ventrolateral medulla (RVLM) increases renal sympathetic activity (RSNA) and blood pressure (BP) in rats. Thus, we hypothesized that CB1 receptor in the RVLM may play a critical role in the development of obesity-induced hypertension. To this end, we evaluated the levels of endocannabinoids and CB1 receptors in the RVLM in high-fat diet (HFD)-induced hypertensive rats. We then used pharmacological and molecular methods to examine the role of RVLM CB1 receptors in regulation of BP, heart rate (HR), and RSNA in obesity-induced hypertensive rats. We found that HFD-fed rats exhibited higher basal BP, HR, and RSNA than standard diet-fed rats, which were associated with increased levels of endocannabinoids and CB1 receptor expression in the RVLM. Furthermore, unilateral intra-RVLM microinjections of AM251 (0, 100, or 500 nM/0.5 μl/site) dose-dependently decreased BP, HR, and RSNA to a greater extent in HFD-fed rats than in standard diet-fed rats. Finally, siRNA-mediated knockdown of CB1 receptor expression in the RVLM robustly decreased BP, HR, and RSNA in HFD-fed rats. Taken together, our results suggested that enhanced CB1 receptor-mediated neurotransmissions in the RVLM may play a role in the development of obesity-induced hypertension.

Abstract 141: Adipocyte Deficiency of Angiotensin Converting Enzyme 2 Increases Systolic Blood Pressures of Obese Female Mice

Background: We demonstrated that sexual dimorphism of obesity-hypertension was associated with differential activity of adipocyte angiotensin-converting enzyme 2 (ACE2) in male versus ( vs ) female mice. These data suggest that adipocyte ACE2 regulates blood pressure by influencing the balance of angiotensin II (AngII, a substrate of ACE2) vs angiotensin-(1-7) (Ang-(1-7)), which differs in male and female mice. We hypothesized that deficiency of ACE2 in adipocytes increases blood pressure of HF-fed female mice. Methods/Results: Mice with adipocyte ACE2 deficiency were developed from breeding Ace2 fl/fl mice to transgenic C57BL/6 mice with heterozygous transgenic expression of Cre recombinase driven by the adiponectin promoter ( Ace2 Adipo ). Female or male Ace2 fl/fl and Ace2 Adipo mice (8 weeks old) were fed a HF (60% kcal as fat) or low fat (LF; 10% kcal from fat) diet for 16 weeks, after which blood pressure was quantified by radiotelemetry. Systolic blood pressures (SBP) were not different in LF-fed female mice of either genotype (24 hr average SBP [mmHg]: Ace2 fl./fl : 121 + 1; Ace2 Adipo : 121 + 1; p&gt;0.05). However, SBP was significantly increased in HF-fed female Ace2 Adipo vs Ace2 fl/fl mice ( Ace2 fl/fl : 127 + 2; Ace2 Adipo : 133 + 3; p&lt;0.05). As AngII is an ACE2 substrate, we quantified blood pressure responses of female mice to an acute challenge of AngII (20μg/kg body weight, sc). AngII administration increased SBPs of LF and HF-fed female mice of both genotypes. However, SBP responses to AngII were augmented in HF-fed Ace2 Adipo female mice compared to HF-fed Ace2 fl/fl controls (baseline vs AngII SBP [mmHg]: LF Ace2 fl/fl : 122 + 8 vs 180 + 4; LF Ace2 Adipo : 127 + 5 vs 173 + 7; HF Ace2 fl/fl : 121 + 3 vs 183 + 3; HF Ace2 Adipo : 138 + 7 vs 197 + 43; p&lt;0.05). In contrast to females, HF-fed Ace2 Adipo male mice had similar SBPs compared to HF-fed Ace2 fl/fl males (24 hour SBP [mmHg]: Ace2 fl/fl : 127±2; Ace2 Adipo : 133±3; p&gt;0.05). Conclusions: Deficiency of ACE2 in adipocytes promoted the development of obesity-induced hypertension in female mice. Moreover, female adipocyte ACE2 deficient mice exhibited augmented blood pressure responses to AngII. These data support the hypothesis that adipocyte ACE2 contributes to sex differences in obesity-induced hypertension.

Adipocyte (Pro)Renin-Receptor Deficiency Induces Lipodystrophy, Liver Steatosis and Increases Blood Pressure in Male Mice.

Adipose tissue dysfunction related to obesity is overwhelmingly associated with increased risk of developing cardiovascular diseases. In the setting of obesity, (pro)renin receptor (PRR) is increased in adipose tissue of mice. We sought to determine the physiological consequences of adipocyte-PRR deficiency using adiponectin-Cre mice. We report a unique model of adipocyte-PRR-deficient mice (PRR(Adi/Y)) with almost no detectable white adipose tissues. As a consequence, the livers of PRR(Adi/Y) mice were enlarged and demonstrated a marked accumulation of lipids. Adipocyte-specific deficiency of PRR increased systolic blood pressure and the concentration of soluble PRR in plasma. To determine whether adipocyte-PRR was involved in the development of obesity-induced hypertension, mice were fed a low-fat or a high-fat diet for 16 weeks. Adipocyte-PRR-deficient mice were resistant to diet-induced obesity. Both high-fat- and low-fat-fed PRR(Adi/Y) mice had elevated insulin levels. Interestingly, adipocyte-PRR deficiency improved glucose tolerance in high-fat-fed PRR(Adi/Y) mice. In response to feeding either low-fat or high-fat diets, systolic blood pressure was greater in PRR(Adi/Y) mice than in control mice. High-fat feeding elevated soluble PRR concentration in control and PRR(Adi/Y) mice. In vitro knockdown of PRR by siRNA significantly decreased mRNA abundance of PPARγ (peroxisome proliferator-activated receptor gamma), suggesting an important role for PRR in adipogenesis. Our data indicate that adipocyte-PRR is involved in lipid homeostasis and glucose and insulin homeostasis, and that soluble PRR may be a predictor of metabolic disturbances and play a role in systolic blood pressure regulation.

Abstract P114: Mas Receptor Deficiency Increases Diastolic Blood Pressure and Reduces Cardiac Function in Obese Female Mice

Objective: We recently demonstrated that protection of female mice from obesity-induced hypertension was associated with increased plasma concentrations of angiotensin-(1-7) (Ang-(1-7)). Ang-(1-7) is a ligand for Mas receptors (MasR), where the peptide has been reported to promote endothelial release of nitric oxide and reduce blood pressure. In this study, we hypothesized that MasR deficiency will abolish protection of female high fat (HF)-fed mice from the development of obesity-induced hypertension. Methods and Results: Female (8 weeks, C57BL/6) wild type (MasR+/+) and whole body MasR deficient mice (MasR-/-) were fed a HF diet (60% Kcal as fat) for 16 weeks. MasR deficiency had no effect on the development of obesity or glucose intolerance in HF-fed female mice. At week 16 of HF feeding, blood pressure was quantified by radiotelemetry. Deficiency of MasR resulted in a significant decrease in pulse pressures of HF-fed females (24hr average: MasR+/+, 37.7 ± 1.5 mmHg; MasR-/-, 33.1 ± 1.0 mmHg; P&lt;0.05). Diastolic blood pressures (DBP) of HF-fed female MasR-/- mice were modestly elevated during the night cycle compared to controls (DBP night: MasR+/+, 91.5 ± 2.0 mmHg; MasR-/-, 96.6 ± 1.3 mmHg; P=0.06). However, systolic blood pressure, mean arterial pressure and heart rate were not significantly different between genotypes. Assessment of left ventricular function by ultrasound demonstrated significant reductions in stroke volume (MasR+/+, 44.3 ± 1.6 μl; MasR-/-, 36.3 ± 2.1 μl), ejection fraction (MasR+/+, 57.1 ± 1.2; MasR-/-, 50.1 ± 2.7%) and fractional shortening (MasR+/+, 29.7 ± 0.8; MasR-/-, 25.3 ± 1.7%) in HF-fed MasR-/- females compared to controls. Conclusion: These results demonstrate that MasR deficiency promotes elevated diastolic blood pressures and reduced cardiac function in obese female mice, suggesting that the Ang-(1-7)/MasR axis protects females from obesity-hypertension. Moreover, these results suggest that MasR agonists may be effective therapies for obesity-associated cardiovascular conditions.

Abstract MP04: In Vivo Bioluminescence Imaging Reveals a Pre-Hypertensive Surge of Nuclear-Factor-κ-B (NF-κB) Activity in the Subfornical Organ (SFO) During Obesity-Induced Hypertension

The central nervous system has been implicated in obesity-induced sympathetic activation and hypertension, although the underlying mechanisms remain unclear. We tested the hypothesis that the transcription factor NF-κB is activated in the SFO, a key cardioregulatory brain center, during the development of obesity-induced hypertension. Male C57Bl/6 mice were instrumented with radiotelemeters for mean arterial pressure (MAP) recording, and underwent SFO-targeted microinjection of an adenovirus encoding firefly luciferase downstream of the NF-κB response elements. After recovery, mice were fed high fat diet (60% fat) or normal chow (5% fat), and SFO NF-κB activity was longitudinally monitored in vivo by bioluminescence imaging coupled with luciferin injections. In response to HFD, a slowly developing hypertension was observed, with an initial rise in MAP at 4 weeks (109 ± 1 vs 117 ± 1 mmHg; day 0 vs day 28; n=8; p&lt;0.05) that was sustained for 8 weeks. NF-κB activity in the SFO increased gradually during HFD feeding, with a surge at 3 weeks, prior to a rise in MAP (day 21: 0.91 ± 0.08 vs 1.70 ± 0.25 photons/s fold baseline; normal chow vs HFD; n=4-7; p&lt;0.05). SFO NF-κB activity transiently subsided and a second elevation was noted during the maintenance of obesity-induced hypertension at 6.5 weeks (day 42: 0.72 ± 0.14 vs 1.52 ± 0.07 photons/s fold baseline; normal chow vs HFD; n=4-7; p&lt;0.05). These findings suggest that NF-κB is activated in the SFO during HFD feeding. The biphasic increase in NF-κB activity prior to and during a sustained increase in MAP suggests a casual role for SFO NF-κB in the development of obesity-induced hypertension. HL63887, HL84207, AHA13POST14410020, K99HL166776

Abstract 317: Mas Receptor Deficiency Increases Blood Pressure Of Female Obese Mice

Objective: We recently demonstrated that female mice were protected from high fat (HF) diet-induced obesity hypertension. Protection of females from obesity-hypertension was associated with an activation of angiotensin converting enzyme 2 (ACE2) in adipose tissue as well as increased plasma concentrations of the ACE2 product, angiotensin-(1-7) (Ang-(1-7)). Previous investigators demonstrated that antagonism of Mas receptors (MasR), receptors for Ang-(1-7)-induced blood pressure regulation, abolished protection of female spontaneously hypertensive rats from angiotensin II (AngII)-induced hypertension. Taken together, these results suggest that activation of MasR protects females from obesity-induced hypertension. We hypothesized that MasR deficiency will abolish protection of female HF-fed mice from the development of obesity-induced hypertension. Methods and Results: Female (8 weeks old, C57BL/6 background) wild type (MasR+/+) and whole body MasR deficient mice (MasR-/-) were fed a HF diet (60% Kcal as fat) for 16 weeks. MasR deficiency had no effect on the development of diet-induced obesity (MasR+/+, 45 ± 2; MasR-/-, 46 ± 2 g). In addition, MasR deficiency had no significant effect on glucose tolerance of HF-fed mice (area under the curve for blood glucose concentrations: MasR+/+, 27766 ± 1675; MasR-/-, 26275 ± 1385). At 15 weeks of HF feeding, carotid artery catheters and radiotelemetry implants were implanted into anesthetized mice, and following 1 week of recovery, blood pressure was quantified for 3-5 days. Deficiency of MasR resulted in a significant increase in diastolic blood pressure (DBP) of HF-fed females compared to controls (24hr average: MasR+/+, 88 ± 2 mmHg; MasR-/, 93 ± 2 mmHg; P&lt;0.05). However, modest elevations in systolic blood pressure (24 hr average: MasR+/+, 125 ± 2 mmHg; MasR-/-, 128 ± 2 mmHg; p=0.38) and mean arterial pressure (24 hr average: MasR+/+, 107 ± 2 mmHg; MasR-/-, 111 ± 2 mmHg; p=0.16) of HF-fed female MasR deficient mice were not statistically significant. Conclusion: Deficiency of MasR promoted elevations in diastolic blood pressure of female obese mice. These results suggest that the ACE2/Ang-(1-7)/MasR axis contributes to protection of obese females from obesity-induced hypertension.

Melanocortin 4 Receptors Reciprocally Regulate Sympathetic and Parasympathetic Preganglionic Neurons

Melanocortin 4 receptors (MC4Rs) in the central nervous system are key regulators of energy and glucose homeostasis. Notably, obese patients with MC4R mutations are hyperinsulinemic and resistant to obesity-induced hypertension. Although these effects are probably dependent upon the activity of the autonomic nervous system, the cellular effects of MC4Rs on parasympathetic and sympathetic neurons remain undefined. Here, we show that MC4R agonists inhibit parasympathetic preganglionic neurons in the brainstem. In contrast, MC4R agonists activate sympathetic preganglionic neurons in the spinal cord. Deletion of MC4Rs in cholinergic neurons resulted in elevated levels of insulin. Furthermore, re-expression of MC4Rs specifically in cholinergic neurons (including sympathetic preganglionic neurons) restores obesity-associated hypertension in MC4R null mice. These findings provide a cellular correlate of the autonomic side effects associated with MC4R agonists and demonstrate a role for MC4Rs expressed in cholinergic neurons in the regulation of insulin levels and in the development of obesity-induced hypertension.

Abstract 624: Chronic High Fat Diet Increases Sodium Reabsorption and αENaC Expression Prior to the Onset of Hypertension in Dahl Salt-Sensitive Rats

An increase in distal nephron-dependent sodium (Na+) reabsorption plays a primary role in the development of obesity-induced hypertension. However, the specific Na+ transporter involved in this process is unknown. The present studies were undertaken to determine the role of the epithelial Na+ channel (ENaC) in the development of high fat-diet (HFD)-induced hypertension. Given that human obesity-induced hypertension is largely salt-sensitive, we chose to expose Dahl salt-sensitive (DSS) rats to either a chronic HFD (42% kcal from fat, normal salt, 0.25%, N=7)) or standard diet (STD, 10% kcal from fat, normal salt, 0.25%, N=7), measure blood pressures (BP) telemetrically, and collect 24 hr urine for Na+ each week, for 4 weeks. In a separate group of DSS rats, we isolated cortical collecting ducts for determination of αENaC protein expression at baseline, 1 week, and 4 weeks following STD or HFD. Telemetric systolic blood pressure (SBP) values increased significantly (P&lt;0.05) from a baseline value of 118±2.7 mmHg to 135±4.4 mmHg after just 2 weeks on the HFD, and to 146.9±2.6 mmHg after 4 weeks (P&lt;0.01). SBPs did not change in DSS rats on STD for the entire 4 weeks. Prior to the increase in BP, 24 hr urine Na+ excretion significantly decreased in DSS rats on HFD compared to STD (0.94±0.15 μmol/min vs. 1.35±0.09, P&lt;0.05). Furthermore, compared to baseline, αENaC protein levels significantly increased after 1 week of HFD [0.93±0.13 and 0.51±0.02 densitometric units (DU) respectively, P&lt;0.01], but not after 1 week of STD (0.46±0.02 DU). Following 4 weeks of HFD, αENaC protein levels remained significantly elevated (0.66±0.05 DU; P&lt;0.05) compared to baseline. These results suggest that increased cortical collecting duct αENaC protein expression may contribute to the reduction in Na+ excretion that initiates the hypertensive cascade in HFD-induced hypertension.

Gamma-MSH/MC3R natriuretic signaling system: The possible explanation for contrasting blood pressure effects of agouti mutation and melanocortin receptor knockout

Overweight and obesity are the major risk factors of arterial hypertension. Recent studies indicate that adipose tissue hormone, leptin, is involved in the development of obesity-induced hypertension. Models of genetically determined obesity in rodents are commonly used to study the pathogenesis of obesity-associated hypertension. One of such models are agouti yellow obese (A y/a) mice which ubiquitously overexpress agouti protein—an endogenous antagonist of melanocortin receptors normally synthesized only in the hair follicle. In A y/a mice, agouti protein is synthesized also in the hypothalamus and blocks the anorectic effect of leptin mediated by alpha-melanocyte-stimulating hormone (α-MSH) which binds to melanocortin type 3 and 4 receptors (MC3R and MC4R). Consequently, A y/a mice are hyperphagic, obese, hyperinsulinemic and hyperleptinemic. Blood pressure is increased in A y/a mice due to increased serum leptin level. In contrast, blood pressure is reduced in MC4R-null mice despite obesity and hyperleptinemia, and is not increased by the administration of leptin in these animals, suggesting an essential role of the melanocortin pathway in the hypertensive effect of leptin. Herein, I propose the hypothesis which might explain why blood pressure is increased in A y/a mice but reduced in MC4R−/− mice, although hypothalamic melanocortin signaling is impaired in both models. According to this proposal, in MC4R−/− mice the natriuretic effect of γ-MSH mediated by intrarenal MC3R is preserved and counteracts prohypertensive mechanisms triggered by leptin. In contrast, in A y/a mice, ubiquitously expressed agouti protein blocks not only hypothalamic MC4R but also renal MC3R and thus impairs γ-MSH-induced natriuresis, leading to blood pressure elevation due to unopposed central and/or peripheral pressor effects of leptin.

Role of endothelin-1 in blood pressure regulation in a rat model of visceral obesity and hypertension.

Endothelial dysfunction has been suggested to play an important role in the development of obesity-induced hypertension. Because endothelin release increases in response to endothelial damage, we examined whether endothelin-1 contributes to increased arterial pressure in a model of visceral obesity produced by feeding Sprague-Dawley rats a high-fat (HF) diet (40% fat w/w, n=6) for 12 months. Arterial and venous catheters were implanted for measurement of mean arterial pressure (MAP) and heart rate (HR) 24 hours per day and intravenous infusions. After a 5-day control period, rats were infused with the selective endothelin-1 type A receptor (ET-A) blocker ABT-627 (2.5 mg/kg per day, IV) for 9 days, followed by a recovery period. Rats fed a standard chow (normal fat, or NF, group: n=6) for 12 months were also infused with ET-A blocker and were used as controls. Compared with NF rats, HF rats had higher MAP (113+/-4 versus 98+/-2 mm Hg), increased visceral fat (18.7+/-2.0 versus 10.8+/-1.4 g), and 3.2-fold increase in plasma leptin despite similar total body weight gain. Long-term ET-A blockade markedly reduced MAP in HF (-14+/-3 mm Hg) and NF (-14+/-2 mm Hg), but it had no effect on HR, GFR, or PRA. These results indicate that a long-term HF diet may cause visceral obesity and increased MAP, even in the absence of major changes in total body weight. Endothelin-1 appears to play an important role in the maintenance of arterial pressure in rats fed HF and NF diets, but it does not appear to contribute to increased MAP in this model of diet-induced hypertension.

Obesity and the kidney connection

The importance of the functional and structural changes that occur in the kidneys in association with obesity was discussed previously in the medical literature.1-4 These studies suggested that the kidneys are involved in the development of obesity-induced hypertension. This involvement is explained by an abnormal tubular sodium handling and by deposition of cells or matrix in the renal medulla that causes an increase in the renal interstitial fluid hydrostatic pressure.3,5

Role of the sympathetic nervous system during the development of obesity-induced hypertension in rabbits.

Role of the sympathetic nervous system during the development of obesity-induced hypertension in rabbits.

C002 Control of blood pressure during the development of obesity-induced hypertension

C002 Control of blood pressure during the development of obesity-induced hypertension

Abnormal pressure natriuresis in the dog model of obesity-induced hypertension.

Obesity is considered to be a major factor in the pathogenesis of hypertension in industrialized countries. Recent studies have suggested that the kidneys may play an important role in the development of obesity-induced hypertension. The purpose of this study was to determine whether obesity-induced hypertension is associated with abnormalities in the pressure-natriuresis relation. Renal function studies were performed in anesthetized control dogs (body weight, 20.2 +/- 0.8 kg) and obese dogs (body weight, 26.4 +/- 0.7 kg) that were maintained on a high-fat diet for 5 to 6 weeks. Mean arterial pressure averaged 122 +/- 5 mm Hg in the control group (n = 6) and 148 +/- 7 mm Hg in the obese group (n = 8). The effects of renal perfusion pressure on renal hemodynamics as well as sodium and water excretions were examined at five levels of renal perfusion pressure ranging from 75 to 165 mm Hg. Pressure-natriuretic and diuretic responses were reduced in the obese dogs by 40% to 50%. The renal blood flow and glomerular filtration rate autoregulatory responses and fractional lithium excretion responses to changes in renal perfusion pressure were similar in the control and obese dog groups. Associated with the attenuated natriuretic response to renal perfusion pressure in the obese dogs were significant elevations in plasma renin activity (4.3 +/- 1.6 versus 1.6 +/- 0.5 ng angiotensin I/mL per hour), plasma aldosterone concentration (34.4 +/- 6.4 versus 15.3 +/- 3.2 ng/dL), and plasma insulin concentration (30.5 +/- 6.8 versus 20.9 +/- 2.9 IU/mL).(ABSTRACT TRUNCATED AT 250 WORDS)