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(Hypertension. 1996;27:926-932.)
© 1996 American Heart Association, Inc.
Articles |
Hypothalamic Lesions Induce Obesity and Sex-Dependent Glomerular Damage and Increases in Blood Pressure in Rats
From the Department of Physiology, West Virginia University, Morgantown, and Department of Pathology, Johns Hopkins Medical School (L.R.), Baltimore, Md.
Correspondence to Chris Baylis, Department of Physiology, West Virginia University, PO Box 9229, Morgantown, WV 26506-9229. E-mail baylis@wvnvms.wvnet.edu.
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Abstract |
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Abstract Placement of two symmetrical lesions in the ventromedial hypothalamus of the rat causes massive overeating and obesity. We have studied male (n=8) and female (n=5) Munich-Wistar rats 7 months after induction of obesity and compared them with age-matched controls. Body weight and kidney weight were greater in control males versus females (396±7 and 1.5±0.1 g versus 229±4 and 1.0±0.1 g, respectively; both P<.001). Both obese males and females were heavier than lean counterparts (592±30 and 361±19 g, both P<.001), whereas kidney weight was similar between obese and control rats of each sex (obese males, 1.5±0.1 g; obese females, 1.1±0.1 g). Blood pressure was higher in obese versus control males; there were no differences between other groups. Single-nephron glomerular filtration rate was similar in control females and males and obese females but depressed in obese males. Glomerular blood pressure was normal in all groups. Urinary protein excretion and the percentage of sclerosed glomeruli were similar in control females and males and obese females but elevated in obese males. Plasma triglyceride levels were elevated in obesity, particularly in males. We conclude that hypothalamic lesioning induces overeating and obesity and selectively in the male causes hypertension and glomerular damage as well as declines in renal function. This injury is not hemodynamically mediated (glomerular blood pressure is normal) but may be related to the elevation in plasma triglyceride levels, which has previously been causally linked to glomerular damage in genetically obese rats.
Key Words: lipids • glomerulus • renal hemodynamics • obesity • hypothalamus
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Introduction |
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Obesity is a major risk factor for cardiovascular disease. The incidence of hypertension increases with obesity,1 and there is also evidence that obesity is associated with glomerular damage in people and animals.2 3 4 It is likely that derangements in plasma lipid profile, ie, elevations in total cholesterol and particularly high triglycerides, contribute to the development of glomerular damage, as indicated by studies in the Zucker rat.4 Indeed, hyperlipidemia is now well recognized to be both a cause and a consequence of progressive renal disease.5 6 Hypertension, specifically when it leads to increases in PGC, provides a separate risk factor for the development of glomerular injury.7
Sex is also a major risk factor for the development of some forms of cardiovascular disease, such as hypertension and coronary artery disease, as well as some forms of glomerular injury, including that produced by advancing age.8 9 10
Bilateral lesions in the satiety center in the ventromedial hypothalamus produce overeating and inactivity, leading to massive obesity.11 This model is an excellent one for most human obesity and has been reported to be associated with glomerular damage, proteinuria, and hypertension.11 12 In the present study, we investigated the long-term effects of ventromedial hypothalamic lesion–induced obesity in male and female rats. Lesioned rats were followed over a 7-month period after lesioning and an equivalent period in controls and were studied by glomerular micropuncture in a terminal experiment.
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Methods |
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Studies were conducted on 30 Munich-Wistar rats derived from a mycoplasma-free colony at Simonsen Laboratories, Gilroy, Calif. Virgin rats of both sexes were studied at approximately 12 months of age. At approximately 4 to 5 months of age, 5 females and 8 males had bilateral, symmetrical electrolytic lesions placed in both ventromedial nuclei of the hypothalamus. Rats were anesthetized with an intraperitoneal injection of an anesthetic consisting of a mixture of 33% methohexital and 67% sodium pentobarbital at a dose of 60 mg/kg BW and were placed in a stereotaxic instrument (David Kopf Instruments). A midline craniotomy exposed the sagittal sinus and surrounding cerebral cortex. The lesions were made with a constant, direct anodal current of 1 mA passed through stainless steel electrodes made from No. 7 insect pins insulated, except for the tips, with Epoxylite varnish. Because of the weight differences between female (202±5 g) and male (321±20 g) rats at the time the lesions were placed, two different atlases of the rat brain were used for determination of the coordinates for lesion placement. Two lesions were made on each side of the hypothalamus, one 0.5 mm from the base of the brain and the other 1 mm directly above the first. The two lesions coalesced to produce a lesion approximately 0.7 mm in diameter and 1.5 mm in height. In female rats, the lesions were placed from 5.3 to 6.2 mm in front of the ear bars,13 and in male rats they were placed from 6.0 to 6.5 mm anterior to the ear bars.14 In all rats, the lesions were located 1.0 mm lateral to the midline of the brain. Rats regained consciousness within an hour after placement of the lesions. Food was withheld until the next day to prevent rats from choking on food eaten before they fully recovered from anesthesia. These lesions produced massive overeating, sedentary behavior, and severe obesity within a few weeks.11 Rats were placed in metabolic cages for measurement of 24-hour urinary protein excretion by the Bradford assay15 before and at monthly intervals after lesioning for 7 months. BW was measured weekly for 1 week before and 4 weeks after lesioning and then at monthly intervals.
Throughout their lives, rats had ad libitum access to drinking water and standard rat chow containing approximately 24% protein and 0.4% sodium and were maintained in positive-pressure laminar flow hoods. The control rats (8 males and 9 females) were aged at Simonsen Laboratories under barrier conditions and with free access to food containing approximately 24% protein and 0.4% sodium. They were shipped to our laboratories approximately 4 weeks before the terminal experiment was conducted and were maintained under conditions similar to those of the lesioned rats. While in our facility, all rats were housed in positive-pressure laminar flow hoods in a dedicated room. These control rats were part of a cross-sectional aging study that has been published recently10 and was conducted over the same time period as the studies on the lesioned rats.
Approximately 7 months after lesioning and at a similar age in controls, the acute study was conducted. On the day of micropuncture, rats were anesthetized with intraperitoneal thiobarbiturate (100 to 120 mg/kg BW; if supplemental anesthesia was necessary, intravenous or intraperitoneal boluses of 5 mg/kg were given as required) and placed on a temperature-regulated table for maintenance of core temperature at 36° to 38°C throughout the experiment. Effective anesthesia was produced in control and lesioned (obese) rats with this dose of thiobarbiturate. The left femoral artery was catheterized and used for periodic blood sampling and monitoring of arterial BP by a pressure transducer connected to a recorder. Immediately after cannulation, 1.2 mL blood was withdrawn and centrifuged, and the red blood cells were rapidly reconstituted in sterile Ficoll solution (13.4%) and returned to the rat. The plasma was stored for less than 48 hours and was assayed for the lipid profile and blood urea nitrogen. The left femoral vein was cannulated for infusion of isoncotic artificial serum (2.5% bovine serum albumin, 2.5% bovine globulin in lactated Ringer's) at 1% BW per hour during the preparatory surgery and thereafter at 0.15% BW per hour for maintenance of plasma volume.10 A tracheostomy was performed and the left jugular vein was catheterized for infusion of [3H]inulin (NEN, 100 µCi/mL, 0.9% NaCl) at approximately 40 µCi/100 g BW per hour. A midline abdominal incision was made and the left kidney was prepared for micropuncture as described earlier.16 The left ureter was cannulated with PE-10 tubing for urine collection directly into graduated tubes. For measurement of PGC by the indirect, stop-flow pressure method, tubule fluid flow was stopped by insertion of paraffin wax blocks into five to seven randomly selected, midproximal surface nephron segments.
After a 45- to 60-minute equilibration period at the end of surgery, two urine collections (20 to 30 minutes) were made, and midpoint femoral arterial blood samples (approximately 50 µL) were taken. Simultaneously, the following measurements and collections were made by micropuncture in the superficial renal cortex: PGC was measured by direct puncture of accessible superficial glomeruli (n=2-4), and indirect PGC in deeper glomeruli was calculated from the stop-flow pressure plus afferent arteriolar oncotic pressure. The stop-flow pressure was measured in the earliest segment proximal to the wax block in the five to seven blocked tubules. As we have reported earlier,10 although indirectly estimated values of PGC tend to be a few millimeters of mercury higher than direct estimates, these values are always close and the relationship is consistent. Since we sampled from two distinct populations of glomeruli, we present the averaged direct and indirect values in each rat to provide an overall value of PGC that is representative of all glomeruli. In addition, hydrostatic pressure was measured in two to three efferent arterioles and in 5 to 10 proximal tubule segments by direct puncture with micropipettes (3- to 4-µm tip diameter) containing 1.2 mol/L NaCl solution. These micropipettes formed part of a servonull micropressure measuring system (model 4a, Instrumentation for Physiology & Medicine) coupled to a pressure transducer and recorder. In addition, five to six exactly timed (approximately 2 minutes) samples of fluid from superficial proximal tubules and samples of blood from three to five superficial efferent arterioles were collected. At the end of the experiment, the left kidney was removed, weighed, sliced longitudinally, and fixed in 10% buffered formalin for later histological and morphometric studies.
The plasma sample taken at the beginning of the acute experiment was analyzed for blood urea nitrogen with kit No. 535 from Sigma Chemical Co, triglycerides with Sigma kit No. 334-uv, and HDL and total cholesterol with Sigma kit Nos. 352-4 and 352, respectively. Activity of [3H]inulin was counted in a liquid scintillation counter in the entire tubular fluid sample, in 5-µL plasma samples, and in 1-µL urine samples. Total protein concentrations in postglomerular (efferent) arteriolar and systemic (femoral) arterial plasma samples were measured by a microadaptation of the method of Lowry et al.17 From these measurements, calculations were made of GFR, SNGFR, single-nephron filtration fraction, glomerular plasma flow, afferent and efferent arteriolar oncotic pressures, Kf, and RA and RE as have been described previously.16
At the end of the experiment, rats were euthanized with an overdose of barbiturate, and brains and kidneys were removed and placed in 10% buffered formalin. After fixation, blocks of kidney tissue were dehydrated and embedded in paraffin, and 3-µm sections were cut and stained with periodic acid–Schiff with Harris hematoxylin counterstain. The tissues were coded and examined for the degree of glomerulosclerosis by light microscopy by two independent observers blinded to the tissue codes. Injury was assessed with a 0 to 4+ scale on at least 100 cortical glomeruli per section. Each section was scored two to three times by each observer and averaged, and the overall average was used. Vg was calculated for each rat from the planar cross-sectional area of 50 undamaged cortical glomeruli measured on a blinded basis. Details of these techniques have been reported previously.10 These Vg measurements were made on immersion-fixed tissue. We have previously validated the use of kidneys fixed by immersion in formalin for Vg measurement.10 The fixed hypothalamus was removed and embedded in paraffin, and 25-µm-thick serial sections were cut and stained with luxol fast blue and cresyl violet.18 The sections were examined for determination of the location and size of each lesion.
All statistical analyses of functional studies were performed with the unpaired t test or appropriate ANOVA. Statistical evaluation of histological data was by Wilcoxon rank sum analysis. Statistical significance was defined as a value of P<.05. All values are expressed as mean±SE. All procedures conducted on rats were in accordance with the West Virginia University guidelines and were approved by the West Virginia University Animal Care and Use Committee.
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Results |
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All of the brain lesions in the experimental rats were symmetrical and located in the same area of the ventromedial hypothalamus. They were approximately 0.7 mm in diameter and 1.5 mm in height. All of the lesions damaged the ventromedial hypothalamic nucleus, and some lesions extended to the base of the brain, the third ventricle, or both.
Fig 1
shows BW changes in male and female Munich-Wistar
rats for 7 months after BVMH lesioning. Cross-sectional data for
normal control rats at approximately 3 to 4, 5 to 6, and 11 to 13
months of age are shown by the open circles. It is clear that obesity
developed rapidly after lesioning in both male and female rats, with
the majority of the weight gain being achieved within the first 6 to 8
weeks after lesioning. As shown in Fig 1, BW was always higher in males
than in females, and the absolute increase in BW was much greater in
males than females. When expressed as a percentage of the prelesioning
BW, the maximum increase in BW at 7 months after lesioning was 86±5%
in males, which was greater than the increase due to age alone seen in
control rats (26±7%). Females with BVMH lesioning showed a maximum
increase in BW at 7 months similar to that of males (82±9%), which
was also greater than the increase due to age alone in control females
(18±4%). Despite the large increase in BW in both male and female
rats with BVMH lesions in the terminal experiment (7 months after
lesioning), wet left kidney weight did not differ in obese versus
control rats of either sex (Table 1). In obese rats,
both BW and left kidney weight were lower in females than males; this
sex difference was also seen in controls (Table 1) and has been
reported previously.10 19
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As shown in Fig 2, measurement of 24-hour urinary total
protein excretion revealed a slowly evolving proteinuria in males with
BVMH lesions that showed a sudden and dramatic increase at 6 months
after lesioning. Females did not develop proteinuria over the 7-month
observation period, and protein excretion in control males and females
showed relatively slight increases due to age alone (Fig 2, Table 1
).
Kidney pathology at 7 months after BVMH lesioning and in
time-matched controls is summarized in Table 2. The
obese males had significantly more glomerular damage than
obese females. Age-matched control male and female rats had
relatively few damaged glomeruli, and at this age (12 months) in normal
rats, there was no sex difference. The glomerular damage in
all rat groups was mainly focal; the frequency of 2+ and 3+
glomerular damage was generally higher, and the incidence
of normal glomeruli was significantly lower in obese males versus all
other groups (Table 2). Vg was greater in
lean males versus females as we showed previously,10 but
there was no difference in Vg between obese males and
females, as Vg fell in obese versus intact males
(P<.01). Additional morphological findings in obese rats
were focal early interstitial fibrosis and tubular atrophy;
most of these foci also had associated edema and mild mononuclear cell
infiltrate, with mild focal tubulitis. Vessels showed mild focal
arteriolar hyaline change but were otherwise unremarkable, except for
focal smooth muscle vacuolization. In two to three rats, a single focus
of intratubular polymorphonuclear leukocytes was seen. All of these
changes were more severe in male versus female obese rats and were
absent in controls.
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The functional studies conducted at 7 months after BVMH lesioning and
in age-matched controls demonstrated that mean arterial
BP (obtained at the time of micropuncture) was elevated in obese males
but not obese females compared with controls (Table 1). Hematocrit was
lower in obese rats versus controls, particularly in males. GFR was
lower in obese than control males and similar to that in both groups of
females when expressed in absolute values and when factored for kidney
weight. GFR was lower in obese versus control males. In contrast,
obesity had no effect on GFR in female rats. As also shown in Fig 2,
the obese males were severely proteinuric at 7 months after lesioning,
whereas all other groups showed similar moderate levels of 24-hour
protein excretion.
Table 3 summarizes values of SNGFR and its determinants.
As at the whole-kidney level, absolute SNGFR was lower in control
females versus age-matched males. Obesity had no effect on absolute
SNGFR in females but lowered SNGFR selectively in males. When factored
for kidney weight, SNGFR was similar in control males and females and
obese females but reduced in obese males. Factoring for kidney weight
is appropriate in this setting because we have shown previously that
glomerular number is similar in male and female
Munich-Wistar rats.19 Glomerular plasma flow
was higher in normal control males versus females, but the difference
was blunted and not statistically significant in obesity. The higher
value of glomerular plasma flow in control males versus
females was due to the lower values of both RA and
RE in males, as we reported previously.19 The
sex differences in RA and RE were abolished by
obesity, mainly because of a rise in RA in obese males
(Table 3). PGC was not different in any of
the four groups despite the rise in systemic BP in obese males (Tables 1 and 3), because the increase in RA in obese males
prevented transmission of elevated BP to the glomerulus. The tubular
pressure and hydrostatic pressure gradient were also similar in all
four groups, as were the oncotic pressures of blood arriving at and
exiting the glomerulus. The mean minimum value of Kf was
also similar in all four groups.
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As shown in Table 4, total cholesterol, HDL
and LDL cholesterol, triglycerides, and blood
urea nitrogen were similar in control males and females at 1 year of
age. In obese males, total cholesterol, HDL
cholesterol, and triglycerides were higher than
in control males and control and obese females, whereas LDL
cholesterol was similar to that in control males and lower
in obese females. In obese females, total cholesterol was
similar to that in controls and LDL cholesterol was
higher versus controls. Triglycerides increased in obesity
in both sexes but by a smaller increment in females versus males. Blood
urea nitrogen levels were similar in all groups.
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Discussion |
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In the present study, mean BP was elevated more than 20% by obesity in lesioned male rats. A close correlation between BW and BP has been reported by many workers, and since weight loss leads to correction of hypertension, obesity is considered to be an important factor contributing to high BP.1 The mechanisms by which obesity increases BP are not known; it has been suggested that peripheral insulin resistance and hyperinsulinemia play a causal role, although there are species variations and some evidence now indicates that insulin resistance is not causal in human or canine obesity-related hypertension.1 All types of hypertension are associated with a rightward shift of the pressure-natriuresis curve, an essential adaptation for preventing massive fluid losses due to the high BP.1 This shift may be primary, causing a sodium-dependent form of hypertension, or may occur as a secondary, compensatory volume-regulatory response.1 Obesity is certainly associated with plasma volume expansion in several species, and our data, showing reduced hematocrit in obese males and females, are also suggestive of an increase in plasma volume. However, studies in obese humans and dogs have shown that BP is not sodium dependent,1 and we recently reported that the conscious obese Zucker rat has an exaggerated rather than blunted natriuretic response to an acute sodium load.20 Furthermore, the hypertension that develops in rats with BVMH lesioning–induced obesity persists in the presence of a low salt diet.12
Although the mechanism of obesity-induced hypertension is not known, it may be influenced by sex because in our study BP rose in obese males, whereas in females, the rise in BP was blunted and did not increase significantly. This difference is unlikely to be due to the developing renal disease in the male, which was still relatively mild at 7 months after BVMH lesioning. Sexual dimorphism is seen in the development of several models of hypertension, including the spontaneously hypertensive rat, the New Zealand genetically hypertensive rat, the deoxycorticosterone acetate–salt model, and the two-kidney, one clip Goldblatt model.21 22 23 24 In all cases, the hypertension is enhanced in the male, and several studies report that castration of the male is protective by reducing BP,21 23 24 although in the deoxycorticosterone acetate-salt and Goldblatt models, ovariectomy also exacerbates the hypertension.23 24
The primary focus of the present study was to investigate the effect of BVMH lesioning–induced obesity on the kidney. We found that the male rat develops proteinuria and kidney damage after a 7-month period of obesity. Despite the increase in systemic BP in obese males, there is no transmission of the increased BP through to the glomerulus, and PGC is not increased versus controls. Therefore, glomerular capillary hypertension is unlikely to be a primary cause of this obesity-related glomerulopathy, although glomerular hypertension has been implicated in the pathogenesis of other forms of progressive glomerular damage.7 25 Studies by O'Donnell and colleagues26 27 have also shown that glomerular injury in the Zucker genetically obese rat occurs in the absence of glomerular hypertension,26 although lowering of PGC will reduce the damage.27 In the present study, we have shown that PGC is not elevated after the glomerular injury process has been initiated. Although we have not specifically tested whether increased PGC precedes the injury, this is unlikely because PGC generally increases as a response to injury; thus, the normal values seen here suggest that this value was never elevated. We have also reported that with advancing age, glomerular damage develops whereas PGC remains normal in the intact male.10 Glomerular hypertrophy also has been suggested as a primary mechanism in the development of some forms of glomerular injury via an increase in glomerular wall tension leading directly to damage.28 However, this possibility is also discounted by our findings in the obese rat because neither kidney weight nor Vg increased in obese versus control males.
A series of elegant studies in the Zucker obese rat have indicated that hyperlipidemia may play a primary pathogenic role in the development of the glomerular damage that occurs in the Zucker obese rat. Chronic administration of lipid-lowering agents reduces the incidence of glomerular damage in male genetically obese Zucker rats,4 and there is now substantial evidence that an atherogenic lipid profile (elevated cholesterol and triglycerides) may predispose to the development of glomerular injury.5 6 In the present studies, we measured total and HDL cholesterol and triglyceride levels in the plasma of rats immediately before acute study. We found that obesity led to a marked increase in total cholesterol, although the increase was in the HDL fraction, with LDL cholesterol showing little change. Serum triglycerides increased markedly in BVMH-lesioned obese male rats, and since the change in cholesterol profile is unlikely to be damaging, the present observations support the concept originating from studies in the obese Zucker rat4 that high triglycerides may underlie the glomerular injury.
In the present study, we observed a sex difference in the response of the kidney to similar degrees of (massive) BVMH lesioning–induced obesity. The glomerular hemodynamic response to obesity by the kidneys of the two sexes was different; in females, RA and RE were similar in obese and lean controls, whereas obesity produced a selective increase in RA in males. We have previously shown that in normal young (4-month-old), 8-, and 12-month-old rats, the female kidney is vasoconstricted compared with that of the male,10 19 although by approximately 19 months of age, RA and RE do not differ between the sexes.10 In the present study, obesity selectively vasoconstricted the kidney in the male, thus abolishing the sex difference in the renal vasculature. The functional consequence of this increased RA in the obese male is that GFR declines. The mechanism of the increase in RA in the BVMH-lesioned obese male is not known but presumably reflects an increased vasoconstrictor tone to the kidney that could be mediated via alterations in endothelial production of eicosanoids, nitric oxide, or endothelin. All of these vascular control systems exhibit sexual dimorphism and are influenced by derangements in plasma lipid profiles; however, at present the exact cause of the increased RA in males made obese by BVMH lesioning remains unknown.
Another finding in the present study is the observation that in the female, no glomerular damage or proteinuria developed 7 months after BVMH lesioning, whereas in the male there was substantial evidence of injury. Considerable evidence suggests that the male is at risk for developing various forms of progressive glomerular disease. In recent studies, we observed that female Munich-Wistar rats develop little glomerular damage or proteinuria with advancing age, whereas intact males exhibit substantial injury10 ; similar findings have been reported by other researchers.29 30 In terms of the general cardiovascular susceptibility of the male sex, the absence of the protective, antiatherogenic estrogens is clearly a major factor.31 In contrast, the male susceptibility to the development of some forms of glomerular damage may be due to the presence of the androgens. In age-dependent glomerular damage, the androgens appear to be the risk factor.10 Male rats also develop ablation-induced glomerular damage more rapidly than females,32 33 and a spontaneous glomerular lesion develops selectively in males of the Munich-Wistar Furth/ZTN substrain of Munich-Wistar rats.34 Glomerular damage is more severe in male versus female obese Zucker rats,35 and the spontaneously evolving glomerular injury in the Imai hypercholesterolemic male rat can be attenuated by castration and restored by testosterone supplementation.36 Clinical studies suggest that women are protected against age-dependent declines in renal hemodynamics and the appearance of glomerular injury.37 Also, the rate of progression toward end-stage renal failure is significantly slower in women versus men with autosomal dominant polycystic kidney disease38 and diabetes and in the presence of hypertensive complications.39 40
In summary, BVMH lesioning produces similar obesity in males and females but hypertension and glomerular damage only in males. The glomerular injury is not due to either glomerular hypertension or hypertrophy and may be related to increases in plasma triglycerides.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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These studies were supported by National Institutes of Health grant HL-31933 (to C.B.) and a Biomedical Research Support Grant (to W.G.). The authors are grateful to Kevin Engels for excellent technical assistance and Maria Guiterrez, who performed some of the lipid measurements and metabolic cage studies during a research rotation in our laboratory.
Received September 20, 1995; first decision October 20, 1995; accepted January 9, 1996.
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