(Hypertension. 1996;27:955-961.)
© 1996 American Heart Association, Inc.
Articles |
Abnormalities of Insulin Receptors in Spontaneously Hypertensive Rats
From the Hypertension Unit, Department of Internal Medicine, University of Udine (Italy) (L.A.S., L.Z., C.C., E.B.); Clinica di Endocrinologia, Universitá di Ancona (Italy) (G.G.); and Division of Endocrinology, San Francisco General Hospital, University of California (L.A.S., C.A.G., G.G., M.S.).
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Abstract |
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Abstract Insulin resistance is present in some strains of rats with genetic hypertension. To determine whether this abnormality is present at the level of the insulin receptor, we compared insulin sensitivity, insulin receptor binding, and mRNA levels in tissues of 10-week-old spontaneously hypertensive rats (SHR) and their normotensive Wistar-Kyoto (WKY) controls. Because we have previously demonstrated an inverse relationship between dietary sodium intake and renal insulin receptor density and mRNA levels in normal Sprague-Dawley rats, the two rat strains in the current experiment were fed either low salt (0.07% NaCl) or high salt (7.5% NaCl) chow until the SHR became hypertensive. Fasting plasma glucose and plasma insulin levels did not differ between SHR and WKY and were not affected by salt intake. When the rats were maintained on the low salt diet, the rate of glucose infusion required to maintain euglycemia during a hyperinsulinemic clamp was significantly lower in SHR than WKY. High salt diet decreased the rate of glucose utilization during the hyperinsulinemic clamp in WKY but not SHR. During the low salt diet, insulin infusion decreased sodium excretion in both WKY and SHR. When the rats were maintained on the high salt diet, the antinatriuretic response to insulin was blunted in WKY but not SHR. Both the density and mRNA levels of insulin receptor were comparable in the kidney of WKY and SHR, but only WKY had the previously demonstrated decrease in receptor number and mRNA levels when fed the high salt chow. Hepatic insulin receptor mRNA levels were significantly lower in SHR than WKY fed the low salt diet. High salt diet decreased significantly insulin receptor mRNA levels in the liver of WKY but not of SHR. Thus, SHR appear to have lost the feedback mechanism that normally limits insulin-induced sodium retention when extracellular volume is expanded. A decreased expression of insulin receptor in the liver of SHR provides a possible explanation for the insulin resistance and decreased insulin clearance present in this strain.
Key Words: insulin • receptors • RNA • liver • kidney • hypertension, genetic
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Introduction |
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Many studies have demonstrated that hyperinsulinemia and insulin resistance occur in patients with essential hypertension,1 2 3 4 5 6 suggesting that insulin might be involved in the pathophysiology of this disorder.7 8 Hyperinsulinemia and insulin resistance are present also in some strains of rats with genetic hypertension, such as the spontaneously hypertensive rat (SHR),9 10 Dahl salt-sensitive rat,11 12 and Milan hypertensive rat,13 suggesting that similar mechanisms might be involved in these experimental models. The relationship between insulin and hypertension, which has been reported in humans and animals with primary hypertension, does not seem to occur in humans4 14 15 and animals16 17 with secondary hypertension. This observation indicates that insulin resistance and hyperinsulinemia are not just consequences of hypertension and that a genetic factor might play a role in both abnormalities. The observation of abnormalities of glucose metabolism in normotensive offspring of hypertensive subjects18 19 20 lends further support to this hypothesis.
Several mechanisms have been postulated to mediate the prohypertensive action of insulin. These mechanisms include stimulation of the sympathetic nervous system,21 growth-promoting activity on vascular smooth muscle cells,22 increase in intracellular calcium level,23 and increase in renal sodium reabsorption.24 With regard to the latter mechanism, experimental studies have shown that insulin increases sodium reabsorption by acting on several distinct segments of the renal tubule.25 26 27 We have recently shown that there is an inverse relationship between dietary sodium intake and renal insulin receptor density and mRNA levels, suggesting the existence of a feedback mechanism that could limit insulin-induced sodium retention when extracellular fluid volume is expanded.28 29 The purpose of the present study was to investigate binding and gene expression of the insulin receptor in tissues of rats with genetic hypertension and whether the relationship between insulin receptor and dietary salt is preserved in these rats.
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Methods |
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Animals
Ten-week-old male SHR and the Wistar-Kyoto (WKY) controls were obtained from Taconic Farms (Germantown, NY). Rats were housed in climate-controlled conditions with a 12-hour light/dark cycle, provided with tap water ad libitum, and fed with chow containing either low salt (0.07% NaCl) or high salt (7.5% NaCl) (Purina Mills) until the SHR developed stable hypertension (4 weeks). Other than NaCl content, the diets did not differ. Systolic pressure was measured in conscious, prewarmed (light lamp), restrained rats by the tail-cuff method with plethysmography and a physiograph recorder (Pulse Amplifier, ITTC Life Sciences). For these measurements, rats were trained adequately before the study. This indirect technique has been shown to be as reliable as direct arterial cannulation in both acute and chronic experiments.30 Rats fasted for 8 hours were killed by decapitation; trunk blood was collected in EDTA-3K for plasma glucose and insulin measurements; and the kidneys were removed, weighed, and snap-frozen in liquid nitrogen for both in situ receptor assay and total RNA isolation. The liver was also removed and frozen for total RNA isolation.
In a separate experiment, WKY and SHR were housed as indicated above and fed with chow containing either low salt (0.07% NaCl) or high salt (7.5% NaCl). When the SHR developed stable hypertension, we performed a euglycemic-hyperinsulinemic clamp study to evaluate insulin-stimulated glucose consumption and the effect of insulin on renal sodium excretion.
Euglycemic-Hyperinsulinemic Clamp
Study
For the
euglycemic-hyperinsulinemic clamp
study, we used a slight modification of the procedure of Finch et
al.31 . On the day of the experiment, rats were
anesthetized with 100 mg/kg thiobutabarbital IP (Inactin,
Andrew Lockwood and Associates) and placed on a heated table to
maintain rectal temperature at 37±0.5°C. Rats underwent tracheostomy
and breathed spontaneously. Thereafter, they were prepared for acute
experimentation as described previously.32 Briefly,
catheters were placed in the right jugular vein for insulin infusion,
the left jugular vein for glucose and saline infusions, and the right
femoral artery for blood sampling and blood pressure monitoring with a
pressure transducer (Gemini 7070, Ugo Basile). A flanged catheter was
placed in the bladder through a suprapubic incision for urine
collection. For replacement of fluid losses during the surgical
preparation, rats received a constant intravenous infusion
of plasma substitute (Hespan, 6% hetastarch in 0.9% NaCl, DuPont
Pharmaceuticals) at a rate of 40 µL/min until a total volume of 0.5%
body weight was administered. The infusion rate was subsequently
adjusted to match urine output. Urine was collected from the bladder in
preweighed polypropylene tubes over a 45-minute period for
determination of baseline urine flow rate and urinary sodium
concentration. Blood was obtained every 15 minutes for glucose
measurement (Accu-check II, Boehringer Mannheim) and at the
beginning and end of this interval for sodium determination. After the
baseline period, rats received an insulin load of 85 mU/kg and a
continuous insulin infusion of 8 mU/kg per minute that produced
comparable plasma insulin levels in WKY and SHR fed with both low salt
and high salt chow. After injection of the insulin bolus, a 25%
glucose solution was infused for a 40-minute stabilization interval
during which blood glucose levels were determined at 5-minute
intervals, and the rate of glucose infusion was adjusted to maintain
the blood glucose level at the average level measured during the
baseline period. Thereafter, a second 45-minute experimental period was
begun, during which urine and blood samples were collected, blood
glucose levels were checked, and the rate of glucose infusion was
adjusted as indicated above.
Insulin Receptor Binding Studies
The distribution and binding characteristics of renal insulin
receptors were assessed by an in situ autoradiographic
technique, as previously described.28 33 Tissue sections
(20 µm) were lyophilized, preincubated twice for 10 minutes in 200
µL KCl (30 mmol/L), incubated for 120 minutes in a
physiological buffer containing 200 pmol/L
125I-Tyr–insulin (2200 Ci/mmol, DuPont-NEN),
rinsed in ice-cold buffer, and dried for 2 hours. Nonspecific
binding was determined by addition to the incubation of 1 µmol/L
unlabeled recombinant human insulin (Humulin R, Eli Lilly). For
determination of binding parameters, adjacent sections were
incubated with 200 pmol/L 125I-Tyr–insulin in
the presence of increasing concentrations of unlabeled insulin (from 10
pmol/L to 1 µmol/L). The amount of radioligand bound to
the tissue sections was determined in a gamma counter. Regional
analysis of insulin binding to glomeruli, renal cortex, and
outer and inner renal medullas was performed on film autoradiographs
obtained by exposing the tissue sections on LKB-Ultrofilm (Leica Inc).
Optical density in the different regions was measured by computerized
microdensitometry. Scatchard analysis of equilibrium binding
data was done with the Ligand program of Munson and
Rodbard34 and resulted in curvilinear profiles indicating
either two classes of receptors (high-affinity, low-capacity;
and low-affinity, high-capacity) or the presence of a single
class of receptors with a negative cooperative hormone-receptor
interaction. In all the experiments, data were analyzed for a
two-site model.
Insulin Receptor mRNA Studies
Total RNA was isolated from frozen tissue by a modification of
the guanidine thiocyanate method of Chirgwin et al35 as
described previously.28 36 The resultant pellet was
dissolved in sterile water and measured by UV absorbance at 260/280
nm.
A 0.92-kb 32P-labeled anti-sense insulin receptor cRNA encoding the 5' end of the rat insulin receptor (rIR) cDNA was synthesized with a PpMu I linearized rIR clone (rIR-p16; a kind gift of Barry J. Goldstein, Joslin Diabetes Center, Boston, Mass).37 Insulin receptor mRNA levels were measured by slot-blot hybridization analysis.28 36 To ensure equivalent loading conditions, we prepared duplicate blots and hybridized them with a 32P-labeled oligonucleotide probe complementary to bases 4011 to 4036 of human 28S ribosomal RNA.28 36
Plasma Glucose, Plasma Insulin, and Serum and Urinary
Sodium
Sodium concentrations in serum and urine were measured by flame
photometry (Klina Flame, Beckman Instruments). Plasma glucose
concentration in trunk blood was determined by the glucose oxidase
method (Beckman Glucose Analyzer). Plasma insulin was measured
by radioimmunoassay (Behring) with a human standard.4 Rat
insulin and human insulin differ by three amino acid residues, so
cross-reactivity of the human antibody with the rat antigen should
be present. To ensure that cross-reactivity was occurring, we
performed radioimmunoassays of serial dilutions of fasting WKY and SHR
plasma with human antibody and compared them with a human-insulin
standard curve. Parallel displacement indicated cross-reactivity of
the two species.
Statistical Analysis
Data are expressed as mean±SE. Comparisons among groups were
done by two-way ANOVA or Student's t test for paired or
unpaired data (StatView) when appropriate. Differences were considered
to be statistically significant when the probability was less than
5%.
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Results |
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Blood Pressure, Body and Kidney Weights, Plasma Glucose, and Plasma Insulin
As shown in Table 1
, blood pressure levels were
significantly higher in SHR than WKY and were affected significantly by
high salt diet only in SHR. Body weight was significantly lower in SHR
than WKY and was increased significantly by the high salt diet in both
groups. SHR had significantly smaller kidneys than WKY as reflected by
a lower ratio of kidney weight to body weight. Kidney weight was
significantly increased by high salt feeding in both groups. Plasma
glucose and plasma insulin did not differ significantly among SHR and
WKY fed low salt and high salt diets (Table 1).
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Euglycemic-Hyperinsulinemic Clamp
Study
Plasma glucose, plasma insulin, and serum sodium did not differ
significantly between rat strains (Table 2). Plasma
insulin levels increased eightfold during the clamp study, but
euglycemia was maintained adequately in all groups studied. During a
low salt diet, the rate of glucose infusion required to maintain
euglycemia during the hyperinsulinemic clamp was
significantly less in SHR than WKY. High salt diet decreased
significantly insulin-stimulated glucose consumption in WKY but not
SHR. Blood pressure was significantly higher in SHR than WKY, was
increased further during the high salt diet only in SHR, and was not
modified by the hyperinsulinemic clamp in any group.
Baseline urine flow rate and urinary sodium excretion were comparable
in SHR and WKY fed both low and high salt chow. During low salt chow,
the hyperinsulinemic clamp induced a significant
decrease in urine flow rate and urinary sodium excretion in both SHR
and WKY. In contrast, during high salt chow, the
hyperinsulinemic clamp induced a significant
antidiuretic and antinatriuretic effect
only in SHR.
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Insulin Receptor Binding Studies
The distribution of 125I-Tyr–insulin
binding in the kidney of WKY and SHR fed low salt and high salt chow is
shown in Fig 1. In all the groups,
radioligand binding was more abundant in renal cortex than
medulla. In the cortex, binding intensity was comparable in glomeruli
and tubules. In the medulla, bound radioligand was found
primarily in longitudinal structures traversing the outer medulla,
presumably corresponding to medullary vascular bundles. The
distribution was comparable in WKY and SHR fed both low and high salt
chow. Nonspecific binding was less than 10% in all the groups.
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When binding data were analyzed for a two-site model, no
differences were found in either the high-affinity,
low-capacity or low-affinity, high-capacity insulin
receptor between SHR and WKY fed a low salt diet (Table 3). When WKY were fed high salt, a significant decrease
in the maximum binding capacity (Bmax) of
the high-affinity receptor was observed compared with WKY fed low
salt (Table 3). The apparent dissociation constant
(Kd) of both receptor sites and the
Bmax of the low-affinity, high-capacity
site did not differ significantly between low salt–fed and high
salt–fed WKY (Table 3). In SHR, the high salt diet did not affect
the number and affinity of both insulin receptor sites (Table 3).
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Analysis of insulin binding to renal cortex, outer medulla, and
inner medulla showed that insulin receptor density was comparable in
all regions of the kidneys obtained from WKY and SHR fed a low salt
diet (Fig 2). In WKY, high salt diet decreased insulin
receptor density in all regions of the kidney, with a
more-pronounced effect in cortex and inner medulla. In SHR, no
effect of salt intake was observed (Fig 2).
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Insulin Receptor mRNA Studies
Slot-blot analysis of insulin receptor mRNA in the
renal tissue of WKY and SHR maintained on a low salt diet revealed
comparable levels (Figs 3 and 4). High
salt diet induced a significant decrease of renal insulin receptor mRNA
levels in WKY but not in SHR (Figs 3 and 4). Hepatic insulin receptor
mRNA levels were significantly lower in SHR than WKY fed a low salt
diet (Figs 3 and 4). High salt diet induced a significant decrease in
insulin receptor mRNA levels in the liver of WKY but not of SHR (Figs 3 and 4).
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Discussion |
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The findings of the present study demonstrate that the density and mRNA levels of insulin receptors in the kidney of SHR do not differ from those in WKY when the rats are fed a low salt diet. Similar to our previous findings in normotensive Sprague-Dawley rats,28 high salt diet decreases the number and mRNA levels of renal insulin receptors in WKY. In contrast, high salt diet does not affect renal insulin receptors in SHR. Evaluation of the renal response to insulin by the euglycemic clamp technique demonstrates that high salt diet decreases the antinatriuretic effect of the hormone in WKY but not SHR. These observations suggest that the feedback mechanism that limits insulin-induced sodium retention in normal rats is impaired in rats with this model of genetic hypertension.
The results of the present study also demonstrate that insulin sensitivity in tissues other than the kidney is reduced in SHR compared with WKY and is not affected by dietary salt intake. Reduced insulin-stimulated glucose utilization is associated with decreased hepatic insulin receptor mRNA levels in SHR fed a low salt diet compared with WKY. In the liver, similar to the kidney, insulin receptor mRNA levels were decreased by high salt diet only in the normotensive rats.
The observation that insulin resistance is present in patients with genetic hypertension1 2 3 4 5 6 and in their normotensive offspring18 19 20 led several investigators to postulate an involvement of insulin in the pathophysiology of this disorder. Strong support for this hypothesis has been provided by studies in animals with experimental models of genetic hypertension.9 10 11 12 13 Among them, the SHR has been extensively studied, and several abnormalities of glucose metabolism have been reported, including hyperinsulinemia,9 10 16 reduced insulin sensitivity,9 10 31 38 39 and decreased insulin clearance by the liver.40 It should be noted that other studies have not uniformly confirmed these findings, in particular, the presence of greater fasting plasma insulin levels in SHR.38 40 41 42 In the present study, no differences in fasting insulin levels were found between SHR and WKY on either low or high salt diet, whereas insulin resistance was demonstrated in SHR by use of the euglycemic-hyperinsulinemic clamp. Although abnormal sensitivity to insulin can be the result rather then the cause of hypertension, normal glucose metabolism and normal response to insulin in rat models of secondary hypertension16 17 make this possibility unlikely.
Decreased sensitivity to insulin may occur for a number of reasons, including defects in insulin binding caused by reduced receptor number or affinity, defects in signal transduction involving receptor autophosphorylation and tyrosine kinase activity, or postreceptor defects at the level of substrates of phosphorylation or effector molecules such as glucose transporters.43 Few studies have addressed the molecular mechanisms of insulin resistance in SHR. Mondon et al44 investigated insulin binding in skeletal muscle, the primary site of insulin resistance in hypertensive rats, and did not find any difference in insulin receptor number or affinity between SHR and WKY. Kahn and Saad45 demonstrated decreased autophosphorylation of the insulin receptor and decreased phosphorylation of insulin receptor substrate IRS-1 in liver and muscle of SHR compared with WKY. The present study demonstrates that hepatic mRNA levels of insulin receptor are lower in SHR than WKY. Insulin binding was not measured in the liver, but it is known that there is a very good correlation between the levels of insulin receptor mRNA and number of receptors.46 Therefore, although insulin resistance of SHR seems to be predominantly located in skeletal muscle,16 the observation of a reduced mRNA for the insulin receptor in the liver suggests a possible molecular mechanism for resistance to the hormone action. Decreased hepatic insulin receptor mRNA levels also provide a possible explanation for the reduced hepatic clearance of the hormone found in SHR.40 Finally, the observation of decreased insulin-stimulated glucose utilization and hepatic insulin receptor mRNA in WKY fed high salt is consistent with the findings of a recent study performed in normotensive men in whom high sodium intake decreased insulin sensitivity.47
In contrast to the findings in liver, no difference in insulin receptors was found in the kidneys of SHR and WKY fed the low salt diet. This is not surprising because it is known that resistance to the action of insulin may differ among target tissues.48 For example, Ferrannini et al1 suggested that the insulin resistance that occurs in essential hypertension is limited to nonoxidative pathways of intracellular glucose disposal. In another study, Finch et al31 demonstrated that SHR maintained on a normal salt diet have a decreased sensitivity to insulin but maintain the same antinatriuretic response to this hormone as WKY. The present study confirms the findings of Finch et al and suggests a possible molecular explanation for the different response in liver and kidney.
The number of insulin receptors in target tissues is regulated by several different hormones and physiological influences.49 A major determinant of both insulin receptor number and gene expression is the ambient insulin concentration (homologous regulation). In addition to insulin, other endocrine and metabolic factors, such as glucagon, growth hormone, glucocorticoid, and ketone concentrations, might affect the insulin receptor number (heterologous regulation).49 In a recent study performed in Sprague-Dawley rats maintained on low (0.07%), normal (0.3%), and high (7.5%) salt diets, we demonstrated an inverse relationship between dietary sodium intake and renal insulin receptor number and mRNA levels.28 This observation suggests the existence of a feedback mechanism that limits insulin-induced sodium retention when extracellular fluid volume is expanded. The present study shows that this mechanism operates normally in WKY and is abolished in SHR. Conceivably, this difference might contribute to the pathophysiology of hypertension in this model. Although extracellular fluid volume and exchangeable sodium are normal in SHR after 8 weeks of age and are thought to play no role in the development of hypertension,50 it is known that the kidneys of these rats need a greater perfusion pressure to maintain normal function51 and that tubular sodium reabsorption is increased, as demonstrated with micropuncture studies and lithium clearance experiments.52 These notions are in keeping with the demonstrated relationship between sodium intake and hypertension in SHR.53 54 Although the role of the abnormal response of renal insulin receptor to dietary sodium in this relationship remains to be clarified, it is interesting that the abnormal response of mRNA levels to high sodium diet was not uniquely found in the kidney but was present also in the liver. Although changes in mRNA levels do not necessarily indicate changes in transcription of the gene, this observation might suggest the presence of a ubiquitous defect in the transcriptional response of the gene to manipulation of dietary salt in SHR and warrants studies on mutations in the 5' flanking region of the insulin receptor gene. It is also interesting that a linkage between a restriction fragment length polymorphism for the insulin receptor gene and essential hypertension has been shown recently.55
In the consideration of possible pathogenic mechanisms that could mediate the prohypertensive effect of insulin, particular attention has been paid to the renal actions of the hormone.24 Insulin regulates sodium reabsorption in rat,24 26 dog,27 56 and human57 58 kidney without affecting renal hemodynamics or glomerular filtration.56 57 58 The exact site of the tubular action of the hormone is still debated. Previous reports have variously indicated an effect of insulin in the proximal tubule,25 distal tubule,27 and loop of Henle.26 Dietary salt modulates insulin receptor number in renal cortex, outer medulla, and inner medulla, indicating an effect on all segments of the renal tubule.28 This mechanism is lacking in SHR and might contribute to an increase in blood pressure, particularly when extracellular fluid volume is expanded or salt intake is increased.
In summary, this study provides a possible molecular explanation for the insulin resistance and reduced insulin clearance found in rats with genetic hypertension. These rats have lost the capability to downregulate insulin receptor in the kidney when extracellular fluid volume is expanded, and this can lead to further sodium retention. This abnormality might be implicated in the development and maintenance of high blood pressure levels in SHR.
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Acknowledgments |
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This research was supported by National Heart, Lung, and Blood Institute grant HL-11046 and Consiglio Nazionale delle Ricerche (C.N.R.) grants 92.01096.CT04 and 94.084231.CT04. L.A. Sechi was the recipient of a Ferrero Foundation grant. G. Giacchetti was the recipient of a fellowship from the Italian Society of Hypertension.
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Footnotes |
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Reprint requests to Leonardo A. Sechi, MD, Hypertension Unit, Department of Internal Medicine, University of Udine School of Medicine, Ospedale Civile, Padiglione Nuove Mediche, 33100 Udine, Italy.
Received November 8, 1995; first decision November 30, 1995; accepted December 26, 1995.
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