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(Hypertension. 1999;34:151-159.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Renal Injury and Salt-Sensitive Hypertension After Exposure to Catecholamines
From the Division of Nephrology, University of Washington Medical Center, Seattle (R.J.J., K.L.G., S.S.), Section Immunology, Department of Internal Medicine, University of Maastricht, Netherlands (A.M.D.), and Division of Nephrology, Loyola University Medical Center, Maywood, Ill, and Hines Veteran Affairs Hospital, Hines, Ill (K.G., A.B.).
Correspondence to Richard J. Johnson, MD, Division of Nephrology, Box 356521, University of Washington Medical Center, Seattle WA 98195. E-mail nephrol{at}u.washington.edu
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Abstract |
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Abstract—We investigated whether chronic infusion of phenylephrine could induce structural and functional changes in the kidney of rats with the subsequent development of salt-sensitive hypertension. Rats were infused with phenylephrine (0.15 mmol/kg per day) by minipump, resulting in a moderate increase in systolic blood pressure (BP) (17 to 25 mm Hg) and a marked increase in BP variability as measured by an internal telemetry device. After 8 weeks, the phenylephrine infusion was stopped with the return of BP to normal, and a nephrectomy was performed for histological studies. Glomeruli were largely spared, but focal tubulointerstitial fibrosis was present, with the de novo expression of osteopontin by injured tubules, macrophage and "myofibroblast" accumulation, and focal increases in mRNA for transforming growth factor ß by in situ hybridization. Peritubular capillaries at sites of injury had distorted morphology with shrinkage, rounding, and focal rarefaction, and endothelial cell proliferation was also identified. Rats were randomized to a high (8% NaCl or 1.36 mol/kg) or low (0.1% NaCl or 17 mmol/kg) salt diet. After 4 to 8 weeks, phenylephrine-treated rats on a high salt diet developed marked hypertension, which was in contrast with phenylephrine-treated rats placed on a low salt diet or vehicle-treated rats given a high salt diet. Hypertension after phenylephrine exposure correlated with the initial mean systolic BP (r2=0.99) and the degree of BP lability (r2=0.99) during the phenylephrine infusion, the amount of osteopontin expressed in the initial biopsy/nephrectomy (r2=0.74), and the final glomerular filtration rate (r2=0.58). These studies provide a mechanism by which a markedly elevated sympathetic nervous system can induce salt-dependent hypertension even when the hyperactive sympathetic state is no longer engaged.
Key Words: phenylephrine • renal circulation • hypertension, episodic • sympathetic nervous system
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Introduction |
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There is ample evidence that a hyperactive sympathetic nervous system (SNS) is present in some forms of human hypertension, especially in early, borderline essential hypertension.1 In addition to the acute effects of SNS activation to raise blood pressure (BP), adrenergic stimulation may induce target organ damage by both hemodynamic and nonhemodynamic mechanisms.2 Adrenergic stimulation can be associated with left ventricular hypertrophy as well as hypertrophy and stiffening of large arteries. Adrenergic agents have also been shown to stimulate vascular smooth muscle cell proliferation and hypertrophy both in vivo and in vitro.3 4
We have been interested in the potential role of the SNS as a mediator of renal injury. It is known that catecholamine infusions can induce acute elevations in glomerular hydrostatic pressure in association with intense renal vasoconstriction and a fall in renal blood flow (RBF).5 6 Infusions of norepinephrine can also induce microalbuminuria in both normal and diabetic individuals.7 A combination of intrarenal and intravenous norepinephrine in dogs resulted in mild tubulointerstitial disease involving 7% of the renal cortex.8 Acute renal failure thought to be secondary to ischemia can also be induced with larger intrarenal doses of norepinephrine.9
One way to examine the effects of chronic adrenergic stimulation is by administering catecholamines chronically to animals. Interestingly, chronic infusions of catecholamines in rats only cause a modest increase (10 to 20 mm Hg) in mean systolic BP,3 10 which is at a level that is usually not associated with renal damage.11 12 However, continuous infusions of catecholamines markedly increase BP lability (defined as the amplitude of BP fluctuations).3 10
In this article we report that chronic infusion (8 weeks) of phenylephrine (PE) in rats results in microvascular injury and tubulointerstitial fibrosis. Although BP returns to normal after the PE infusion is stopped, persistent hypertension redevelops on a high salt diet. The clinical relevance of this new finding to human hypertension is discussed.
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Methods |
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Experimental Protocol
Studies were designed to examine the acute and postinfusion effects of PE on BP and renal structure in the rat. For these studies, BP was measured in unrestrained and unanesthetized rats with the use of radiotelemetry, with BP readings obtained continuously at 10-minute intervals.13 BP was obtained over a 7- to 14-day period after the installation of the radio transmitters, after which the rats received PE (30 to 35 mg/kg per day or 0.15 mmol/kg per day SQ) continuously by minipump for 8 weeks. A control group received only vehicle. At the end of 8 weeks, the PE infusions were stopped and the pumps were removed. The rats underwent removal of 1 kidney for histological studies and after 1 to 2 weeks were placed on either a high salt (8% NaCl or 1.36 mol/kg) or low salt (0.1% NaCl or 17 mmol/kg) diet for an additional 4 to 8 weeks. The control rats also underwent nephrectomy and were then placed on a high salt diet for the second 6 to 8 weeks. In addition to histological studies, serum (for creatinine) and urine (collected overnight in metabolic cages) were obtained before the PE infusion, 2 weeks after the PE infusion was started, 2 weeks after the PE infusion was stopped, and at the end of the study. Finally, at the time of death both RBF (transonic probe) and glomerular filtration rates (GFR) (by inulin clearances) were measured. The study was performed in accordance with guidelines for the humane use of laboratory animals by the National Institutes of Health.
PE Infusions
PE (Sigma Chemical) was constituted in 0.2% ascorbate in
Ringer's lactate3 and infused by subcutaneous minipump
(Alzet, model 2002, Alza Corp) at a rate of 0.15 mmol/kg per day
in Sprague-Dawley rats (male; weight, 225 to 300 g; Charles
River). Pumps were replaced at 30 days.
Continuous BP Measurements
Rats were anesthetized with pentobarbital sodium and
underwent laparotomy with the placement of a BP sensor catheter in the
aorta above the renal arteries with fixation of the radiofrequency
transmitter to the peritoneum (model TA11PA-C40, Data Sciences). After
surgery, rats were housed in individual plastic cages, where the
signals from the pressure sensor were converted, temperature
compensated, and sent through the radio transmitter to the telemetry
receiver placed under the cage. The receiver was connected to a BCM-100
consolidation matrix, which entered the information into the Dataquest
IV acquisition system, which recorded and displayed the BP
measurement every 10 minutes for the duration of the
study.13
From the recordings, mean systolic BP could be determined for any given day. In addition, BP variability (amplitude of BP fluctuations) was calculated as the SD for mean systolic BP measurements, and the severity of labile hypertension was defined as mean systolic BP ±1 SD.
Immunohistological Studies
Renal biopsies were collected in methyl Carnoy's fixative,
processed, paraffin-embedded, sectioned (4 µm), and
immunostained by indirect immunoperoxidase
staining14 with the following primary antibodies: ED-1
(Serotec), a monoclonal IgG1 to rat
macrophages, monocytes, and dendritic cells; 
sm-1 (1A4), a
monoclonal IgG2a to -smooth muscle actin (a
marker of renal interstitial myofibroblasts) (Sigma);
OP199, a goat anti-rat osteopontin antibody (gift of C. Giachelli);
goat anti-human and anti-bovine type IV collagen (Southern Biotech);
monoclonal antibody F37.2D12, an antibody to human renin (gift of M.
Laprade, Sanofi Recherche, Montpellier, France); and RECA-1, a
monoclonal anti-rat endothelial
antibody.14 15 Detection of antigens was followed by
incubation with a biotinylated secondary antibody directed against the
primary antibody, followed by avidin-biotin-peroxidase,
diaminobenzidine, and colorimetric reaction, as
detailed previously. Controls included omission of the primary antibody
or substitution with an irrelevant antibody of the same species and
isotype.
Capillary endothelial cell proliferation was detected by double immunostaining tissue sections with the RECA-1 antibody and an antibody to the proliferating nuclear cell antigen (PCNA) (19A2, a monoclonal IgM; Coulter) as described elsewhere, again with the use of controls in which either primary antibody was substituted with an irrelevant monoclonal antibody of the same isotype.15
In Situ Hybridization for Transforming Growth Factor
ß
Mouse transforming growth factor (TGF)
ß1 cDNA corresponding to 974 bp (421 to 1395)
(gift of H.L. Moses, Vanderbilt University, Nashville, Tenn) was
transcribed into 35S-labeled antisense and sense
cRNA probes. In situ hybridization was then performed on formalin-fixed
tissue as described.16
Quantification of Histological Findings
Tubulointerstitial injury was graded 2
different ways. The first method used a blinded semiquantitative
scoring system (0 to 5)14 as follows: grade 0, no
increased tubular cellularity, basement membrane thickening, tubular
dilation, atrophy, sloughing, or interstitial widening;
grade 1, <10% increased tubular cellularity, basement membrane
thickening, dilation, atrophy, sloughing, or interstitial
widening; grade 2, 10% to 25%, as above; grade 3, 26% to 50%; grade
4, 51% to 75%; and grade 5, >75%. For each biopsy, the
entire cortical and juxtamedullary regions were evaluated under low
power (x100), and a mean score per biopsy was calculated. The second
method is based on experimental observations that osteopontin
expression by injured tubules is a sensitive marker of
tubulointerstitial injury in experimental and human
disease.17 18 Using computer-assisted image
analysis software (Optimas, version 6.2, Media Cybernetics), we
measured the percent area occupied by osteopontin-positive tubules
(including the entire cortical and juxtamedullary regions) per field
(4 mm2) at x50, and a quantitative
measurement for the mean percent area was calculated for each
biopsy.19
In addition, the percentage of glomeruli with juxtaglomerular renin immunostaining was determined in each biopsy. Previous studies from our group have shown that this measurement correlates semiquantitatively with tissue renin content.20
Renal Functional Studies
At the end of the study, rats were anesthetized with
intravenous pentobarbital and surgically prepared for GFR
measurements by inulin clearance.13 The femoral vein was
cannulated with polyethylene tubing (PE-50), and a priming dose of
inulin was administered, followed by a continuous infusion of 150
mmol/L NaCl containing inulin to maintain a plasma inulin concentration
of 0.1 mmol/L (50 mg/dL). The contralateral femoral vein and
ureter were then cannulated, followed by a 150-mmol/L NaCl bolus equal
in volume to 1% of the body weight. This was then followed by an
infusion of 0.055 mL/min for the replacement of surgical and ongoing
fluid losses. Two 20-minute clearances of inulin were obtained, with
the midpoint used for each urine collection. Inulin
concentrations were measured spectrophotometrically by the
diphenylamine method, and the GFR was calculated with the use of
standard formulas.13 RBF was measured with a 1.0-mm
Transonic R series flow probe that was placed around the renal
artery.13 Serum creatinines were measured by
autoanalyzer. Urinary protein was measured by sulfosalicylic
acid precipitation.18
Statistical Analysis
Comparison between groups was made by the Mann-Whitney test,
Student's t test, or ANOVA with Fisher's correction when
indicated.
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Results |
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PE Infusion Results in Severely Labile Hypertension
The infusion of PE resulted in a modest (17 to 25 mm Hg) increase in mean systolic BP and a marked increase in BP variability (Table 1). Representative BP tracings (measured by continuous telemetry) in rats receiving PE and in a control rat are shown in Figure 1. Although the mean systolic BP was modestly elevated, rats receiving PE exhibited large spontaneous fluctuations in systolic BP, with frequent readings >180 mm Hg (Table 1, Figure 1).
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Renal Structural and Functional Changes Are Induced With PE
Infusion
At the end of 8 weeks of PE infusion, rats underwent nephrectomy
for histological studies. Light microscopy demonstrated
focal renal injury in rats receiving PE that was primarily in a striped
pattern radiating into the cortex from the outer medulla (Figure 2). Glomeruli were relatively well
preserved, although occasional glomeruli showed glomerular
collapse consistent with ischemia. Afferent arterioles
and interlobular arteries also showed some thickening with occasional
hyalinosis. Juxtaglomerular renin content tended to be
higher than in control rats but did not reach significance (Table 2). The most dramatic findings related to
the tubulointerstitium. Many tubules were atrophic or dilated,
and there was an influx of mononuclear cells into the interstitium,
with widening of the interstitial space (Figure 2A, Table 2). In addition, there was marked upregulation of the
macrophage adhesive protein osteopontin by both proximal and
distal tubules in areas of injury (Figure 2B). An infiltration
of macrophages (ED-1+ cells) was also present near the
sites of osteopontin expression (Figure 2C).
Interstitial cells expressing -smooth muscle actin,
consistent with a "myofibroblast" phenotype, were
also present (Figure 2D). There was also increased
expression of TGF-ß mRNA noted by in situ hybridization in the areas
of striped fibrosis (Figure 2E and 2F), and this was associated
with interstitial deposition of type IV collagen (Figure 2G). Control rats displayed minimal abnormalities.
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The integrity of the microvasculature (glomerular and peritubular capillaries) was assessed by immunostaining for the endothelial cell–specific marker RECA-1. Whereas control rats had a normal, lacy pattern of capillaries encircling the tubules, PE-infused rats demonstrated focal areas of altered capillary morphology, with shrinking and rounding of capillaries and focal rarefaction (Figure 3A and 3B). Capillary endothelial cell proliferation (identified by RECA-1 and PCNA double staining) was also focally observed in the capillaries in or near the sites of injury (Figure 3C), whereas it was practically absent in control kidney tissue.
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The infusion of PE was also associated with a modest rise in the serum creatinine and a slight increase in urinary protein excretion (Table 1).
Salt-Sensitive Hypertension Develops in Rats After PE
Exposure
At the end of 8 weeks, the PE infusion was stopped, and the pumps
were removed. Systolic BP and BP variability quickly returned
to the normal range (Table 1, Figure 1). Rats were
subsequently placed on a high salt (8% NaCl) or low salt (0.1% NaCl)
diet within 1 to 2 weeks after discontinuation of the PE infusion.
Systolic BP steadily rose to hypertensive levels in the rats on
a high salt diet that had previously received PE. In contrast,
systolic BP increased slightly but still remained within the
normotensive range in PE-treated rats that were placed on a low salt
diet, as well as in control rats that had received vehicle and then
were placed on a high salt diet (Table 1).
Rats were maintained on the high and low salt diets for up to 8 weeks and then were killed for additional functional and histological studies. Seven of the 13 rats who received a high salt diet developed severe hypertension and were killed after only 4 to 6 weeks of the high salt diet. As shown in Table 1, PE-treated rats that were placed on a high salt diet had greater urinary protein excretion than either PE-treated rats on a low salt diet or control (vehicle-treated) rats on a high salt diet. The final GFR also tended to be lower in both PE-treated groups, although it was significant only in the low salt group (Table 1). In contrast, the RBF was significantly lower in both PE-treated groups, being 50% reduced in the low salt group and 30% reduced in the high salt group (Table 1).
Histological studies obtained at the time of death
continued to show evidence of tubulointerstitial
damage (Table 2). Although focal areas of
tubulointerstitial damage persisted, they appeared
less when compared with tissue obtained at the end of the PE infusion.
The decrease in injury noted by routine light microscopy was also
associated with less osteopontin, -smooth muscle actin, and TGF-ß
expression (Table 2 and data not shown). Glomeruli also remained
normal, although occasional glomeruli in the high salt group showed
glomerular collapse or focal synechiae and the early
development of segmental sclerosis.
Correlations
An analysis was performed to identify factors that could
predict the subsequent BP response to the high salt diet in the rats
treated with PE. Both the mean systolic BP and the severity of
labile hypertension (defined as the mean BP +1 SD) during the PE
infusion strongly correlated with the subsequent BP response to a high
salt diet (r2=0.987 and
r2=0.986, respectively;
P<0.0001). The degree of
tubulointerstitial damage in the initial biopsy
also could predict the subsequent development of hypertension with a
high salt diet in PE-treated rats. Although the correlation was
relatively weak by standard periodic acid–Schiff scores of
tubulointerstitial damage
(r2=0.471; P<0.003), it
was improved when the correlation was made with the osteopontin scores
(r2=0.744; P<0.001)
(Figure 4). Interestingly, RBF at the
time of death did not correlate with the final BP in PE-treated rats on
a high salt diet, although the final GFR did show a weak correlation
(r2=0.582; P<0.003).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We report a new model of salt-sensitive hypertension induced by the chronic exposure (8 weeks) of rats to catecholamines (ie, PE). Infusion of PE resulted in severe labile hypertension and the development of focal microvascular and tubulointerstitial damage in the kidney. When the PE infusion was stopped, both mean BP and BP variability returned to normal, but the subsequent exposure to a high salt diet led to the redevelopment of hypertension. The degree of BP elevation correlated with the BP during the PE infusion and also with the degree of tubulointerstitial damage induced.
The first observation was that the dose of PE used resulted in severe
labile hypertension. The overall mean systolic BP during the PE
infusion was only 140 to 145 mm Hg. However, there was a dramatic
increase in BP variability, an observation that has been noted
previously,3 10 resulting in frequent BP elevations of
170 mm Hg (Figure 1). The finding of mildly elevated
mean systolic BP with episodic fluctuations is often used to
define the syndrome of borderline hypertension, which is also linked
with an elevated SNS,1 and is also reminiscent of
pheochromocytoma, another elevated catecholamine
state.21 22
The second observation was that a focal
tubulointerstitial lesion was induced with the PE
infusion. The tubulointerstitial damage often
appeared in stripes radiating out from the outer medulla, suggestive of
a vascular pattern of injury (Figure 2). Glomeruli were
generally spared, although some glomeruli displayed capillary collapse
consistent with renal ischemia. However, the major
finding was of focal tubular injury with dilation and cast formation
and with focal accumulations of macrophages,
-actin–positive fibroblasts, and TGF-ß expression and collagen
deposition. In addition, there was an alteration in the peritubular
capillary morphology at the sites of injury, with rounding, shrinkage,
and focal rarefaction. There was also some evidence of capillary
repair, as documented by the presence of proliferating capillary
endothelial cells in or near the sites of damage
(Figure 3). These histological findings are
similar to those observed with other types of
tubulointerstitial injury, such as
glomerulonephritis, urinary tract obstruction, and
cyclosporine toxicity, with aging, and in various
hypertensive models.14 17 23 24
The observation that PE could induce chronic tubulointerstitial disease is of interest. The dose of PE used resulted in mean systolic BP in a range (142 to 145 mm Hg) not generally considered to induce renal damage, at least in humans.11 12 We have also reported that rats with 2-kidney, 1 clip hypertension do not develop glomerular and tubulointerstitial injury in the unclipped, hypertensive kidney if the mean systolic BP is <160 mm Hg.20 However, PE infusion markedly stimulated BP variability, leading to labile hypertension (Figure 1), and it is possible that the renal damage was due to the episodic elevations in pressure. Although the glomerulus and distal capillary beds are thought to be protected from elevations in BP as a result of the process of renal autoregulation in which the afferent arteriole and interlobular artery vasoconstrict,25 this autoregulatory response is not instantaneous, and some transmission of pressure may occur. Indeed, micropuncture studies have documented that norepinephrine infusion will cause significant increases in glomerular and peritubular capillary hydrostatic pressure.5 Sudden elevations in BP might be expected to induce some peritubular capillary damage, especially because these capillaries are without surrounding pericytes.
Norepinephrine and PE can also cause marked renal vasoconstriction, and micropuncture studies have documented a 30% to 40% decrease in peritubular capillary blood flow.5 Whether this reduction in blood flow is sufficient to cause local ischemia to the surrounding tubules and interstitium is unclear, but it is of interest that similar reductions in RBF have been observed with other agents that also cause tubulointerstitial damage, including angiotensin II, cyclosporine, and nitric oxide synthase inhibitors.23 24 26 It is also possible that PE could be inducing some of its effects through nonhemodynamic mechanisms, because it is known, for example, that catecholamines can induce smooth muscle cell hypertrophy and proliferation in vitro.4
The major new finding was that despite the transient return of both mean systolic BP and BP variability to normal on cessation of the PE infusion, the subsequent placement of the rats on a high salt diet resulted in the redevelopment of hypertension. Interestingly, the hypertension persisted despite histological evidence that the renal injury was lessening (Table 2). This suggests that alterations in the ability of the kidney to excrete salt were induced by the PE infusion. Several mechanisms could be operative, including renal injury, which is known to activate renal afferents and stimulate central SNS activity (reviewed in Reference 2727 ); local osteopontin expression, which may inhibit intrarenal nitric oxide generation28 ; and peritubular capillary damage and interstitial fibrosis, both of which could shift the pressure natriuresis curve to the right.29 The lower GFR observed might also contribute to a relative impairment in salt excretion, although it is known that glomerulotubular balance will maintain sodium excretion despite moderate changes in GFR.30
This study may be relevant to the natural history of pheochromocytomas, in which it is known that surgical removal is more effective at curing hypertension in the early phases when the hypertension is episodic and there is less evidence of target organ damage.21 22
These studies may also provide a potential pathogenic pathway to
explain the linkage between SNS overactivity and the subsequent
development of persistent hypertension.1 However, the
model would have to be considered an accelerated version of what occurs
in humans, because the BP lability in this model is more severe than
that typically observed in human labile hypertension, and the
development of persistent hypertension is also more rapid.
Nevertheless, this model may be relevant to the hypertension that
occurs in blacks, in which evidence for involvement of the SNS includes
a greater pressor response to exercise31 and to
norepinephrine,32 which may relate to
increased -adrenergic responsiveness.33 The
salt-sensitive hypertension that characterizes this population is
associated with substantial renal injury, characterized by
arteriolosclerosis, glomerulosclerosis,
tubulointerstitial fibrosis, and a reduction in the
GFR,34 findings similar to those observed in our
experimental study. Another example is obesity-associated hypertension,
which is associated with SNS activation,35 salt-sensitive
hypertension, and renal damage with
glomerulosclerosis and
tubulointerstitial fibrosis.36
Similarly, one might speculate that the routine but sometimes marked
fluctuations in BP that occur daily in "normotensive"
patients37 and that are known to be triggered by the
SNS38 may be relevant to the age-related development of
glomerulosclerosis and
tubulointerstitial fibrosis,39 the
age-related decline in GFR, and the development of salt-sensitive
hypertension in this population.40 Finally, one wonders
whether a similar mechanism may be involved in the transition from
labile to persistent hypertension that occurs in "white-coat"
hypertension,41 with sleep apnea,42 or with
exercise-induced hypertension,43 all of which are
SNS-driven responses. Although certainly speculative, the studies
presented here are consistent with recently proposed
mechanisms for the development of persistent hypertension in
humans.29 44
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Acknowledgments |
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This study was supported by US Public Health Service grants DK-43422, DK-47659, DK-52121, and DK-40426. Dr Suga was supported by a Banyu fellowship and the Kanae Foundation for Life and Socio-Medical Science.
Received January 14, 1999; first decision February 19, 1999; accepted March 11, 1999.
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