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Am J Physiol Heart Circ Physiol 293: H2537-H2542, 2007. First published August 10, 2007; doi:10.1152/ajpheart.01081.2006
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Obesity augments vasoconstrictor reactivity to angiotensin II in the renal circulation of the Zucker rat

David W. Stepp,1,2 Erika I. Boesen,1 Jennifer C. Sullivan,1,3 James D. Mintz,1 Clark D. Hair,1 and David M. Pollock1,2,4

1Vascular Biology Center and Departments of 2Physiology, 3Pharmacology, and 4Surgery, Medical College of Georgia, Augusta, Georgia

Submitted 2 October 2006 ; accepted in final form 7 August 2007


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Obesity is an emerging risk factor for renal dysfunction, but the mechanisms are poorly understood. Obese patients show heightened renal vasodilation to blockade of the renin-angiotensin system, suggesting deficits in vascular responses to angiotensin II (ANG II). This study tested the hypothesis that obesity augments renal vasoconstriction to ANG II. Lean (LZR), prediabetic obese (OZR), and nonobese fructose-fed Zucker rats (FF-LZR) were studied to determine the effects of obesity and insulin resistance on reactivity of blood pressure and renal blood flow to vasoconstrictors. OZR showed enlargement of the kidneys, elevated urine output, increased sodium intake, and decreased plasma renin activity (PRA) vs. LZR, and renal vasoconstriction to ANG II was augmented in OZR. Renal reactivity to norepinephrine and mesenteric vascular reactivity to ANG II were similar between LZR and OZR. Insulin-resistant FF-LZR had normal reactivity to ANG II, indicating the insulin resistance was an unlikely explanation for the changes observed in OZR. Four weeks on a low-sodium diet (0.08%) to raise PRA reduced reactivity to ANG II in OZR back to normal levels without effect on LZR. From these data, we conclude that in the prediabetic stages of obesity, a decrease in PRA is observed in Zucker rats that may lead to increased renal vascular reactivity to ANG II. This increased reactivity to ANG II may explain the elevated renal vasodilator effects observed in obese humans and provide insight into early changes in renal function that predispose to nephropathy in later stages of the disease.

renal blood flow; insulin resistance; microcirculation

OBESITY IS EPIDEMIC IN INDUSTRIALIZED nations, resulting in insulin resistance (IR), hypertension, and renal disease. Although end-stage renal disease is heavily influenced by the diabetes that develops later in the lives of obese patients, mounting evidence indicates that obesity and IR may also impair renal and vascular function before the onset of diabetes (9, 27). The window between the development of obesity and the onset of frank type II diabetes may represent an early therapeutic opportunity to address renal vascular health, but the nature of the alterations in renovascular function early in obesity is not well-understood, and mechanisms of such alterations remain unknown.

One potential mechanism by which renal injury may occur in obese/diabetic individuals is an inappropriate overstimulation of the renin-angiotensin system (RAS). Experiments in animals indicate that blockade of RAS improves renal damage and longevity in rat models of obesity (17, 26, 35). The cellular targets of the RAS are controversial and may include effects on renal tubules, glomerular cells, or the kidney vasculature. Recent data from human studies suggest that vascular responses to the RAS are perturbed in obese humans. Obese individuals show a greater increase in renal blood flow to angiotensin-converting enzyme (ACE) inhibition (1) or angiotensin receptor blockade (25) and pressor reactivity to angiotensin (ANG II) has been shown to be increased in obese men (22). In the obese Zucker rat (OZR) model, pressor responses to ANG II have also been found to be increased, further indicating that vasoconstrictor reactivity to ANG II may be increased in obesity (2, 37). Direct documentation of this enhanced constrictor reactivity, however, is lacking, and potential mechanisms underlying a change in reactivity are unclear.

The current study tests the hypothesis that vasoconstrictor sensitivity to ANG II is increased in the renal circulation in prediabetic obesity. The OZR model was chosen as it exhibits a long period of IR before the development of diabetes (38) and shows early evidence of renal injury (11, 18). Specificity of changes in ANG II reactivity was assessed with comparison to norepinephrine (NE; a different constrictor) and the mesenteric circulation (a different vascular bed). The influence of underlying IR was examined separately from obesity as a mechanism by determining renal vascular reactivity to ANG II in the nonobese, fructose-fed rat (FF-LZR) model of IR. The role of chronic low renin was assessed by comparing renal vascular reactivity to ANG II in rats on a normal and low-salt diet. Taken together, these studies provide the first exploration of in vivo renal vascular constrictor reactivity in an animal model of obesity and provide new insights into possible mechanisms in obesity-induced alterations in renovascular function.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals. Lean (LZR) and obese (fa/fa OZR; Harlan Teklad) Zucker rats 16–18 wk of age were used in all experiments and fed 0.28% NaCl standard rat chow and tap water ad libitum except where described below. The fa/fa strain was selected due to its slow onset of diabetes and its protracted period of IR. In a separate group of LZR, IR independent of obesity was induced by feeding a 0.35% NaCl, 66% fructose diet as described previously (Harlan Teklad; Ref. 28). LZR were used in the fructose feeding protocol to avoid variance in genetic background between groups. Fructose feeding was begun ad libitum at 8–9 wk of age and continued for 8 wk. To counter the effects of salt intake and lowered renin, rats were fed a 0.08% salt diet ad libidum (Harlan Teklad). Low-salt diet began at 13–14 wk of age and continued 4 wk in both LZR and OZR to elevate plasma renin activity (PRA). Rats were housed in the American Association of Laboratory Animal Care-approved animal care facility of the Medical College of Georgia, and the Institutional Animal Care and Use Committee approved all protocols.

In vivo hemodynamics. Assessment of hemodynamics and vascular reactivity were performed in isoflurane-anesthetized animals as described previously (28, 30). Briefly, anesthesia was induced using 2% isoflurane in an induction chamber followed by delivery via a nose cone for the remainder of the experiment. Animals were maintained on a supplemental oxygen stream (100%) and allowed to breathe independently. Body temperature was maintained at 37°C with a heating pad servocontrolled by a rectal thermistor. Arterial pressure was assessed with a fluid-filled catheter advanced into the thoracic aorta via the left carotid artery, and heart rate was calculated using a cardiotachometer from the aortic pressure signal. In separate groups of animals, renal and mesenteric blood flows were measured using ultrasonic flowmetry with a 1PR flow probe placed around the renal and superior mesenteric artery, respectively (Transonic). Acoustic coupling was maintained with conductance jelly. All data were recorded using Windaq data acquisition hardware and software (DATAQ). Vascular resistance was derived by dividing the pressure signal by the flow signal using the ACODAS software add-on for Windaq. Resistance values were normalized to organ weight in grams (determined post mortem), and changes were expressed as percent of baseline resistance. To remove potentially confounding sympathetic innervations, animals were treated with the nicotinic antagonist mecamylamine (2 mg/kg) to block ganglionic transmission as described previously (30). Bolus administrations of experimental agonists were injected intravenously in random order to avoid ordering effects. Because plasma volume does not track body size in obese rats and plasma volumes are similar between LZR and OZR (30), drug injections were based on drug weight in micrograms, and identical masses were injected in all groups of rats.

Metabolic studies. Nonfasting blood glucose concentrations were assessed with a Precision Glucometer (Medisense, Bedford, MA). Plasma total cholesterol and triglycerides were assessed with colorimetric assays from WAKO Chemicals. Lipid peroxides were assessed with a colorimetric assay from Calbiochem. Plasma insulin was determined using the Mercodia Rat Insulin ELISA assay from ALPCO Diagnostics. Assessment of urine and sodium excretion was performed by placing rats in Nalgene metabolic cages for rodents. Rats were maintained in the cages for 72 h to acclimate, and then data were collected over the next 24 h. PRA was measured by radioimmunoassay (GammaCoat 125I Plasma Renin Activity Radioimmunoassay Kit; DiaSorin, Stillwater, MN).

Statistics. All data are presented as means ± SE. Differences in means among groups for nonrepeated variables (plasma measures, baseline hemodynamics) were compared by one-way ANOVA. Differences in means among groups with repeated variables (changes in arterial pressure, changes in vascular resistance) were compared by one-way ANOVA with repeated measures. Dunnett's test was used as the post hoc test.

Chemicals and reagents. All drug reagents were obtained from Sigma Chemical. Isoflurane was obtained from Webster Veterinary Supply.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Baseline characteristics of lean, obese, and fructose-fed rats. Table 1 summarizes plasma chemistry and hemodynamic and renal characteristics of LZR, OZR, and FF-LZR. OZR were heavier and had larger kidneys relative to LZR and FF-LZR. Under isoflurane anesthesia, OZR display a modest elevation in mean arterial pressure (MAP), and FF-LZR displayed a modest tachycardia compared with LZR controls. Renal blood flow was elevated in OZR, but this appeared to reflect primarily the larger kidney size as vascular resistance normalized to renal mass was similar in all three groups.


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  		Table 1. Hemodynamic and metabolic parameters

 
Ganglionic blockade with mecamylamine lowered blood pressure and heart rate in all groups, consistent with sympathetic withdrawal (Table 1). The effect was significantly greater (21%) in OZR in agreement with previous reports of greater sympathetic tone in metabolically dysfunctional animals (6, 30). Sympathetic withdrawal lowered renal vascular resistance similarly in all three groups, indicating that the larger drop in blood pressure likely reflects preferential sympathetic withdrawal elsewhere in the circulation.

In addition to hemodynamic alterations, OZR displayed marked changes in renal function. Food and water consumption and urine volume were increased in OZR relative to LZR, consistent with hyperphagia and polydipsia as previously reported in this model (12, 20). Thus sodium consumption was elevated in OZR as was sodium excretion. Renal function in FF-LZR was similar to that observed in LZR.

Plasma chemistry confirms the well-established metabolic syndrome in both OZR and FF-LZR as indicated by hyperinsulinemia, hypercholesterolemia, hypertriglyceridemia, and elevated nonesterified free fatty acids. In addition, OZR show reduced levels of PRA, consistent with previous reports in OZR (2, 8, 15). PRA values in both LZR and OZR on low-salt diet exceeded the upper limits of the assay (~30 ng·ml–1·h–1 ANG II).

Blood pressure responses to ANG II. Pressor reactivity to ANG II in LZR and OZR are shown in Fig. 1. Maximum pressor responses to ANG II are elevated in OZR relative to LZR in the absence of mecamylamine when sympathetic reflexes are intact (Fig. 1A). This finding confirms previous reports that pressor responses to ANG II are increased in the OZR (2). After ganglionic blockade and the loss of reflex control of blood pressure, responses to ANG II are increased in LZR (maximum pressor response = 71 ± 4 vs. 91 ± 5 mmHg, pre- and postmecamylamine; P < 0.05), consistent with loss of baroreflex restraint of pressor increases. Responses in OZR were not affected by ganglionic blockade (maximum pressor response = 89 ± 4 vs. 81 ± 12 mmHg, pre- and postmecamylamine; P = not significant), consistent with previous reports of impaired baroreflex control in OZR (3, 5, 23). After mecamylamine, pressor reactivity to ANG II was no different between LZR and OZR (Fig. 1B). The finding suggests that augmented pressor responses observed in the intact state do not reflect generalized vasoconstrictor sensitivity to ANG II but a lack of baroreflex restraint in OZR. To avoid confounding effects of variable sympathetic influence on the examination of vascular resistance, all experiments were performed after ganglionic blockade.


Figure 1
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  		Fig. 1. The effect of obesity on angiotensin II (ANG II) induced increase in mean arterial pressure (MAP). A: pressor response before ganglionic blockade with mecamylamine. B: pressor response after ganglionic blockade. n = 9; *P < 0.05. The lack of significant differences in B suggests that differences observed in A reflect altered sympathetic control of blood pressure by impaired baroreflexes.

 
Renal vascular reactivity. Peak renal vasoconstrictor responses to bolus injections of ANG II are shown in Fig. 2. The increase in renal vascular resistance in response to bolus doses of ANG II was markedly increased in OZR compared with LZR. Because these experiments were performed in the absence of changes in sympathetic tone and similar changes in renal perfusion pressure, this finding suggests that there is a direct increase in vascular reactivity to ANG II in the renal circulation in the OZR. In contrast, there was no increase in reactivity to ANG II in insulin-resistant FF-LZR. This finding suggests that IR, independent of obesity, is not sufficient to provoke an increase in the reactivity to ANG II.


Figure 2
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  		Fig. 2. The effect of obesity and insulin resistance on changes in renal vascular resistance to ANG II. n = 9; *P < 0.05. The lack of significant differences in the fructose-fed group (insulin resistance without obesity) suggests that insulin resistance is not the likely explanation for the significant differences observed in obese rats.

 
Specificity of increased renal vascular sensitivity to ANG II. To determine whether the heightened reactivity to ANG II was specific to ANG II, two additional experiments were performed. First, reactivity to an alternative vasoconstrictor, NE, was examined in LZR and OZR. The results of these experiments are shown in Fig. 3A. NE was less potent than ANG II in promoting renal vasoconstriction in LZR (maximum response = 418% ± 42% vs. 679% ± 64% increase in NE vs. ANG II; P < 0.05), but responses in OZR were not significantly different from those seen in LZR. As reported previously (30), pressor reactivity to NE was similar between LZR and OZR when reflex control of pressure was eliminated (maximum response = 81 ± 5 vs. 89 ± 7 mmHg, LZR vs. OZR; P = not significant).


Figure 3
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  		Fig. 3. The effect of obesity on adrenergic reactivity in the renal circulation (A) and reactivity to ANG II in the mesenteric circulation (B). n = 7. The lack of significant differences in A or B suggests that the effects of obesity on the renal circulation are specific to ANG II and the renal vasculature. NE, norepinephrine.

 
The second assessment of specificity was to compare reactivity to ANG II in the mesenteric circulation in LZR vs. OZR. Changes in vascular reactivity to ANG II were less potent in the mesenteric circulation in both LZR (maximum response = 124% ± 28% vs. 576% ± 64%, increase in mesenteric vs. renal; P < 0.05) and OZR (maximum response = 94% ± 23% vs. 1,352% ± 238%, increase in mesenteric vs. renal; P < 0.05). Reactivity to ANG II in the mesenteric circulation was comparable between LZR and OZR (Fig. 3B), indicating that the potentiation of responses to ANG II observed in the renal circulation was not generalized.

Effect of a low-salt diet. The effects of a low-salt diet on baseline hemodynamics in LZR and OZR are shown in Table 2. In anesthetized animals, there was no significant effect of low-salt diet on MAP, heart rate, renal mass, renal blood flow, or resistance. This observation is consistent with previous reports that increased blood pressure in the OZR is independent of salt intake (2, 24). As seen during normal salt intake, the decrease in blood pressure following ganglionic blockade was greater in OZR than LZR, but the magnitude of the decrease in both LZR and OZR was decreased compared with normal salt controls. This observation is consistent with previous work showing that the high renin state associated with a low-salt diet blunts the sympathetic contribution to acute control of arterial pressure (19, 34). The low-salt diet had no effects on plasma measures of IR in either LZR or OZR (data not shown).


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  		Table 2. Hemodynamic parameter effects of low-salt diet

 
The effect of a low-salt diet on renal reactivity to ANG II is shown in Fig. 4. Four weeks of low-salt diet had no effect on renal vascular sensitivity to ANG II in LZR but markedly suppressed increases in renal vascular resistance to ANG II in OZR. This finding suggests two conclusions. First, that renin activity and, by extension, plasma angiotensin levels contribute to vascular sensitivity to ANG II in the kidney as levels fall. Increases in PRA appear to have little effect in LZR, suggesting that a threshold exists at which vascular reactivity to ANG II begins to increase. Second, the low-salt diet reversed ANG II vascular reactivity in OZR. This observation suggests that the low PRA observed in OZR may play a causal role in the heightened vascular sensitivity to ANG II observed in these animals.


Figure 4
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  		Fig. 4. The effect of a low-salt diet on renal vascular reactivity to ANG II. n = 6; *P < 0.05. The lack of significant differences between the low-salt conditions [in lean (LZR) and prediabetic obese (OZR) Zucker rats] and LZR on a normal salt diet suggest that lowering salt, and thereby raising renin and ANG II, eliminates the effects of obesity on renal vascular reactivity to ANG II.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The goals of this study were to test the hypothesis that obesity increases renal vascular sensitivity to ANG II and identify potential underlying mechanisms. The key findings of this study are: 1) increases in renal vascular resistance in response to ANG II are augmented in obesity; 2) the heightened reactivity to ANG II is specific to ANG II and the renal circulation; and 3) the mechanism does not involve IR per se but may reflect increased ANG II sensitivity secondary to chronically low PRA. The key elements of discussion relevant to these findings are the Zucker rat as a model of obesity and renal injury and the underlying mechanisms of increased vascular reactivity to ANG II.

Obesity in the Zucker rat model occurs secondary to a mutation in the leptin receptor, resulting in hyperphagia. This ~40% increase in food consumption results in the accumulation of visceral and subcutaneous adipose tissue and subsequent IR. Although leptin has been largely discounted as a cause of hyperphagia in humans, the net result in both the rat model and the human population is the same: excess food intake, weight gain, and insulin insensitivity. Furthermore, Zucker rats show renal dysfunction as early as 12 wk of age, as indicted by increased microalbuminuria (11), and this is further evident at 20 wk of age, spanning the time frame used in these studies (10). Renal damage progresses over the life of the Zucker rat and is the most common cause of early death in this rat strain. A key advantage of the fa/fa OZR strain is the lack of pancreatic failure and a delay in the development of diabetes until later in life, allowing a large window of time to assess the effects of IR and obesity on renal vascular function before the onset of frank type II diabetes and chronic hyperglycemia. Given that obese human patients show renal dysfunction before the onset of diabetes and fixed hyperglycemia, the effects of obesity and metabolic dysfunction in the prediabetic state are of particular interest.

The mechanisms of renal injury in the prediabetic state remain elusive, but mounting evidence argues for a role of the RAS. Treatment with inhibitors of ACE or angiotensin II receptors have been shown to reduce glomerular injury, decrease urine albumin levels, and prolong the life of Zucker rats (17, 26, 35). The mechanisms by which angiotensin inhibition might prevent renal injury are numerous but include direct effects of ANG II on renal tissue and vascular and/or tubular alterations in reactivity to ANG II. Although evidence exists that obesity increases glomerular, mesangial, and tubular reactivity in ANG II stimulation (13, 14, 36), the effects of obesity and IR on the renal vascular response to ANG II have not be explored. In the current study, we report that renal but not mesenteric vascular reactivity to ANG II is increased in OZR. This augmented response is not due to differences in baseline resistance because, whereas flow was higher in the OZR, renal vascular resistance was similar. This response is specific to ANG II, as adrenergic reactivity appears unaffected. These findings provide the first insight into renal vascular constrictor reactivity in the setting of obesity and metabolic dysfunction.

Three aspects of obesity that are present in OZR provide potential mechanisms for altered renovascular sensitivity to ANG II: modulation of constriction by sympathetic nerves, IR, and chronically low renin. The existence of increased sympathetic modulation of vascular resistance is evident in the OZR by the greater drop in arterial pressure with ganglionic blockade. This finding is underscored by an increase in renal sympathetic nerve activity observed by Morgan et al. (21). However, whereas augmented pressor reactivity to ANG II has been reported in intact OZR (2) and also observed in our results, the increased pressor response is normalized by ganglionic blockade. This finding suggests that altered sympathetic modulation of vascular resistance, most likely due to blunted baroreflexes (3, 23), accounts for the increased pressor reactivity. This does not indicate a generalized increase in vascular responsiveness, however. A comparison of mesenteric vs. renal vascular sensitivity to ANG II in LZR and OZR in the current study indicates that generalized changes in vascular reactivity are not evident. To rule out sympathetic modulation of vascular responsiveness in our studies, changes in vascular resistance were evaluated in the functional absence of sympathetic innervation by chemical sympathectomy with mecamylamine. Under these conditions, renal vascular reactivity to ANG II is markedly increased. Thus, whereas OZR certainly possess alterations in sympathetic control of some vascular beds, this cannot account for increased reactivity to ANG II observed in the current study.

IR is a cardinal feature of obesity and has been associated with impairment in vascular function in other vascular beds. In the current study, we examined renal vascular function in the fructose-fed rat, a model of IR without obesity that has been shown to display increased aortic constrictor reactivity to ANG II (16, 32). Despite these observations, we found no difference in reactivity to ANG II in the renal circulation of fructose-fed rats compared with LZR. We draw two conclusions from this observation. First, whether there is conduit artery hyperreactivity in the fructose-fed rat, it does not extend into the renal microcirculation. This may reflect a variety of factors including differences in conduit and renal microvascular smooth muscle phenotype and differences in the hemodynamic forces between the aorta and the renal vasculature. Second, these data suggest that IR, as an independent variable, does not promote changes in renal vascular reactivity to ANG II. Thus it seems that the IR observed in OZR is an unlikely mechanism for the heightened sensitivity to ANG II observed in the renal microcirculation.

A third possibility is the low levels of PRA observed in OZR. This decrement has been reported previously in OZR (2, 8, 15) and is further confirmed by our results. Conceptually, a decreased PRA level and concomitant drop in ANG II would cause an increased sensitivity to ANG II, maintaining normal RAS control of renal circulation. Previous studies from Ruan et al. (29) demonstrated that renal vascular ANG II receptor expression, as assayed by RT-PCR and radioligand binding, was reduced and increased on low- and high-salt diet diets, consistent with this concept. Other aspects of renal function in the OZR also appear to show increased sensitivity to ANG II, including proximal tubule sodium pump activity (31), activity of the sodium-hydrogen exchanger (4), and natriuresis (14). In the current study, we used a low-salt diet that has been shown to increase renin by 10-fold and observed that sensitivity to ANG II was normalized in OZR with no effect on LZR. This finding lends strong support to the idea that the lower PRA may serve as a trigger to increase ANG II sensitivity in the renal circulation of the OZR.

This observation raises many intriguing questions. Why is renin activity decreased in OZR? A simple answer is that salt intake is increased in OZR, and, indeed, the current study finds a ~40% increase in salt intake. However, the large drop in renin (50%) seems inconsistent with such a relatively moderate increase in sodium intake. Is beta-adrenergic control of renin release preserved in OZR? Sensitivity to beta-adrenergic stimulation in cardiac and fat tissue is reported to be reduced in OZR (7, 33) and may also be reduced in the macula densa. Finally, does the modest hypertension in OZR contribute to downregulated renin and thus increased reactivity to ANG II? Understanding how the various determinants of renin expression and secretion are altered in obesity and result in decreased PRA represents a key next step in understanding the relationship between obesity, altered renin, and hypersensitivity to ANG II in the renal circulation.

In summary, the current study has determined that vasoconstrictor reactivity to ANG II is specifically increased in the renal circulation. This augmented sensitivity cannot be accounted for by IR or impaired sympathetic regulation of vascular tone. A low-salt diet corrects this alteration, suggesting that the low renin observed in the OZR leads to chronically low ANG II and compensatory upregulation of ANG II reactivity in the renal circulation. The extent to which this altered reactivity contributes to renal injury remains to be determined.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
We gratefully acknowledge the support of National Heart, Lung, and Blood Institute Grants HL-76533 (D. W. Stepp) and HL-69999 and American Heart Association Grant EIA-0340443N (D. M. Pollock).


   ACKNOWLEDGMENTS
 
We gratefully acknowledge the technical assistance of Julie Campbell.


   FOOTNOTES
 

Address for reprint requests and other correspondence: D. W. Stepp, Vascular Biology Center, Medical College of Georgia, 1459 Laney Walker Blvd., Augusta, GA 30912 (e-mail: dstepp{at}mcg.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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