(Hypertension. 1995;25:399-407.)
© 1995 American Heart Association, Inc.
Articles |
Decreased Glomerular Basement Membrane Heparan Sulfate Proteoglycan in Essential Hypertension
From the Medizinische Klinik II (B.H., C.M., U.R., H.M., H.-G.S.) and the Institut für Klinische Chemie und Pathobiochemie (G.S., E.S., H.G., H.-D.H.) der RWTH Aachen (Germany).
Correspondence to Dr med Bernhard Heintz, Medizinische Klinik II, RWTH Aachen, Pauwelsstraße 30, 52057Aachen, Germany.
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Abstract |
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Abstract Heparan sulfate proteoglycans are major components of the glomerular basement membrane and play a key role in the molecular organization and function of the basement membrane. Moreover, their presence is essential for maintenance of the selective permeability of the glomerular basement membrane. Recently, we isolated and characterized a novel small basement membrane–associated heparan sulfate proteoglycan from human aorta and kidney. Partial amino acid sequence data clearly show that this heparan sulfate proteoglycan is distinct from the large basement membrane–associated heparan sulfate proteoglycan (perlecan). Using specific monoclonal antibodies, we have shown that the novel heparan sulfate proteoglycan is located predominantly in the glomerular basement membrane and, to a lesser extent, in the basement membrane of tubuli. Turnover or, in the course of kidney diseases, degradation of heparan sulfate proteoglycan from glomerular basement membranes may lead to urinary excretion of heparan sulfate proteoglycan, which can be measured by a sensitive enzyme immunoassay. The aim of the present study was to analyze whether changes in the structure and function of glomerular basement membranes can be directly detected by measurement of the excretion of a component of this basement membrane, eg, heparan sulfate proteoglycan into urine. The excretion of this small heparan sulfate proteoglycan was compared after physical exercise in normotensive and hypertensive subjects. Normotensive subjects and treated, essential hypertensive patients underwent a standardized workload on a bicycle ergometer. Biochemical characterization of the urinary proteins and heparan sulfate proteoglycan was performed before and 15 and 45 minutes after exercise. In both groups, physical exercise induced a significant increase in the excretion of urinary
1 microglobulin and albumin. However, a 10-fold
increase in the urinary excretion rate of heparan sulfate proteoglycan
was seen in normotensive subjects under exercise. In hypertensive
patients, the relative increase in heparan sulfate proteoglycan
excretion was significantly diminished (P<.05). These data,
supported by immunohistochemistry, indicate changes in the glomerular
basement membrane of the kidney in hypertension. Therefore,
determination of urinary excretion of this novel small heparan sulfate
proteoglycan after exercise may be a sensitive marker for the detection
of basement membrane alterations in hypertension.
Key Words: heparitin sulfate • hypertension, essential • proteoglycans • exercise • proteinuria
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Introduction |
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Heparan sulfate proteoglycans are major components of the glomerular basement membranes and play a key role in their molecular organization and function (reviewed in References 11 and 22 ). The presence of heparan sulfate proteoglycans is essential for maintenance of the selective permeability of the glomerular basement membrane. Loss of the anionic sites provided by the heparan sulfate proteoglycans is associated with proteinuria and has been observed in a number of nephropathies.3 4 5 6 7 Recently, we isolated and characterized a novel small basement membrane–associated heparan sulfate proteoglycan from human aorta and kidney. Partial amino acid sequence data clearly show (Table 1) that this heparan sulfate proteoglycan is distinct from the large basement membrane–associated heparan sulfate proteoglycan (perlecan). Using specific monoclonal antibodies, we showed that this heparan sulfate proteoglycan is located predominantly in the glomerular basement membrane and, to a lesser extent, in the basement membrane of tubuli but also in the mesangium. Although in humans no data on the turnover of basement membrane heparan sulfate proteoglycans are available, results from an experimental rat model indicate that heparan sulfate proteoglycans in the kidney undergo a rapid turnover.8 9 10 In the present study, we show that release of heparan sulfate proteoglycans from the glomerular basement membrane leads to urinary excretion of heparan sulfate proteoglycans in humans, which can be measured by a sensitive enzyme immunoassay. The aim of the present study was to compare urinary excretion of this small heparan sulfate proteoglycan after physical exercise in normotensive and hypertensive subjects. Although our data show a strong increase in the excretion of heparan sulfate proteoglycans during exercise in normotensive subjects, this increase is less pronounced in hypertensive patients, indicating changes in the glomerular basement membranes of the kidney in hypertension.
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Methods |
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The protocol of the study was in accordance with the declaration of Helsinki, and full informed consent was obtained. The institutional ethics committee approved the study protocol.
The effects of mild exercise on urinary proteins and heparan sulfate proteoglycans were studied in 17 normotensive subjects (41±2.8 years) and 17 treated, essential hypertensive patients (44±2.7 years) who underwent a standardized workload on a bicycle ergometer applied for 2 minutes (139±6.7 versus 136±6.7 W). The intensity of the workload was chosen by the use of a protocol published recently to standardize short-term exercise according to age, sex, and body surface.11 The anthropometric data showed no significant differences between the two groups (Table 2). Table 3 shows the particulars of the hypertensive patients and the workload applied.
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The subjects were hydrated 30 minutes before exercise by drinking 0.5 L of water. A catheter was inserted into a forearm vein to collect blood samples before and 15 and 45 minutes after exercise. Urine samples stabilized with 0.05% sodium azide were collected before and 15 and 45 minutes after exercise.
The urinary protein excretion rates and ratios12 13 14 were
measured before and 15 and 45 minutes after exercise. Urine creatinine
was measured by an automated Jaffe method; protein was measured by a
biuret method (Boehringer). The molecular weight of the urinary
proteins was characterized by a modified semiautomated microscale
sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE
Phast system, Pharmacia) described by Kierdorf et al.15
Albumin (microalbumin) and -1 microglobulin were measured with a
quantitative enzyme immunoassay (Elias).
Heparan Sulfate Proteoglycan
Novel small heparan sulfate proteoglycans were isolated from
human aorta and kidney and characterized biochemically and
immunochemically (manuscript in preparation). Briefly, heparan sulfate
proteoglycan was purified from human aorta and kidney by several
chromatographic steps. Heparan sulfate proteoglycan isolated from the
aorta revealed an Mr distribution of >200 to 80
kd; for the small heparan sulfate proteoglycan from the kidney, the
Mr distribution was 160 to 30 kd. The sizes of
the core proteins were determined to be 24 and 22 kd for aorta and
kidney, respectively. The monoclonal antibody 1F10/B8 (see below)
recognizes both core proteins. However, small heparan sulfate
proteoglycans from the kidney and aorta can be discriminated according
to their different sizes, which result primarily from differences in
their glycosaminoglycan chain moieties. Amino acid sequence
analysis of the small heparan sulfate proteoglycans was performed
according to standard procedures. Briefly, purified heparan sulfate
proteoglycans were digested with trypsin, and fragments were separated
by reversed-phase chromatography. Amino acid sequence analysis was
performed by automated Edman degradation with an Applied Biosystems
Sequencer No. 470A. Partial amino acid sequence data clearly show
(Table 1) that this heparan sulfate proteoglycan is distinct from the
large basement membrane–associated heparan sulfate proteoglycan
(perlecan). Cloning and sequencing of the core protein of this heparan
sulfate proteoglycan are currently in progress.
Heparan Sulfate Proteoglycan Enzyme Immunoassay
Monoclonal antibodies were raised against the small heparan
sulfate proteoglycan from human aorta in mice according to standard
procedures. A sensitive enzyme immunoassay for heparan sulfate
proteoglycan was developed with one of these antibodies (1F10/B8).
Briefly, the polyanionic heparan sulfate proteoglycan from the sample
was bound on a cationic charge–modified microtiter plate (kindly
provided by Greiner). Nonspecific binding sites were blocked by 2% fat
dry milk powder (BLOTTO) in phosphate-buffered saline (PBS). Bound
heparan sulfate proteoglycans were detected by the heparan sulfate
proteoglycan–specific monoclonal antibody 1F10/B8. Bound antibody was
detected by the use of a second peroxidase-labeled polyclonal goat
anti-mouse antiserum (Dako). For heparan sulfate proteoglycan excreted
into urine, data were expressed either as nanograms per minute of
heparan sulfate proteoglycan or as the ratio of heparan sulfate
proteoglycan and creatinine (micrograms per millimole). All samples
were measured at least in duplicate. No inhibition of binding was
observed in this assay when other polyanionic molecules such as heparin
or keratan sulfate proteoglycans were added in control experiments.
Immunohistochemistry
For immunohistochemical studies, methanol/ethanol-fixed
cryosections of kidneys from hypertensive patients and normotensive
subjects were used. After fixation, endogenous peroxidase was blocked
by incubation with 1% H2O2 for 30 minutes.
Incubation with primary antibody 1F10/B8 was performed for 1 hour at a
concentration of 10 µg/mL PBS supplemented with 1% bovine serum
albumin/0.1% Triton/0.1% Tween 20 (wt/vol/vol). After rinsing,
sections were incubated with peroxidase-conjugated rabbit anti-mouse
immunoglobin antiserum (Dako). After rinsing with PBS,
peroxidase-labeled sections were treated with 1.26 mmol/L DAB and
0.01% H2O2/L for 3 to 5 minutes.
Hemalum was used for counterstaining. The specificity of the staining
was controlled by the use of isotypic antibodies.
Statistics
The data were analyzed with the nonparametric Mann-Whitney
U test to compare heparan sulfate proteoglycan excretion and
excretion rates for hypertensive patients and normotensive subjects.
The Wilcoxon test for paired data was used to compare basal values and
values after exercise. Results are expressed as mean±SEM. The null
hypothesis was rejected when P<.05.
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Results |
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Patients
Despite an effective antihypertensive treatment, all systolic and diastolic blood pressure values were significantly elevated in the hypertensive patients compared with healthy control subjects (P<.05). The highest mean blood pressure value was 174/87±3/3 mm Hg in normotensive subjects compared with 192/99±4/2 mm Hg in the hypertensive patients (P<.05) (Fig 1). Nevertheless, the change in blood pressure at rest to the peak value after exercise showed no significant difference between the two groups.
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Measurement of Heparan Sulfate Proteoglycan and Proteins in
Urine
Heparan sulfate proteoglycan concentrations in urine were measured
with a sensitive enzyme immunoassay. No differences were found in the
basal levels of the heparan sulfate proteoglycan excretion and in the
creatinine clearance between hypertensive patients and normotensive
subjects (Table 3). The mean resting ratios of urinary heparan sulfate
proteoglycan to creatinine excretion in the hypertensive patients and
control subjects were 4.53±1.34 and 3.74±1.29 µg/mmol, respectively
(P>.05). During exercise, the ratio of heparan sulfate
proteoglycan to creatinine excretion increased significantly
(P<.05), up to 37.3±12.2 µg/mmol (45 minutes after
exercise) in normotensive subjects; the increase in hypertensive
patients, up to 30.3±13.3 µg/mmol, was less pronounced
(P<.05). Comparable results were obtained when the data are
given as heparan sulfate proteoglycan excretion rates. In the
hypertensive patients and control subjects, baseline values were 24±8
and 28±8 ng/min, respectively (P>.05). During exercise,
the heparan sulfate proteoglycan excretion rate increased significantly
(P<.05), up to 235±77 ng/min (45 minutes after exercise)
in normotensive subjects and to 190±83 ng/min in hypertensive patients
(P<.05). Fig 2 shows a comparison of the
increase of the urinary heparan sulfate proteoglycan excretion. In both
groups, no significant correlation was found between the increase in
systolic or diastolic blood pressure and the increase in heparan
sulfate proteoglycan excretion rate or the ratio of heparan sulfate
proteoglycan to creatinine excretion. In addition, the ratio of heparan
sulfate proteoglycan to albumin excretion showed an increase after
physical exercise. The albumin-creatinine excretion ratio showed no
difference in the resting conditions (0.156±0.035 mg/mmol in
hypertensive patients versus 0.176±0.036 mg/mmol in normotensive
subjects). However, the increases in the albumin-creatinine excretion
ratios under physical exercise (up to 0.42±0.10 mg/mmol in
hypertensive patients versus 0.872±0.46 mg/mmol in normotensive
subjects) were statistically significant in both groups. Similar
results were obtained when albumin excretion rates were calculated. The
albumin excretion rates showed no difference in the resting conditions
(0.98±0.22 µg/min in hypertensive patients versus 1.11±0.23
µg/min in normotensive subjects). However, the increases in the
albumin-creatinine excretion ratios under physical exercise (up to
2.65±0.63 µg/min in hypertensive patients versus 5.51±2.84 µg/min
in normotensive subjects) were statistically significant in both groups
but also between hypertensive patients and normotensive subjects
(P<.05). For the 1 microglobulin excretion, a smaller
but significant increase was found in normotensive subjects; the
increase failed to reach significance in hypertensive patients (Table 4).
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Tamm-Horsfall Protein
The SDS-PAGE separation of urinary proteins showed in most but not
all individuals a peak in the range of 90 kd 15 and 45 minutes after
exercise (Fig 3). The quantitative determination of the
Tamm-Horsfall (THF) protein excretion ratio, which showed a significant
increase after exercise from 188±84 to 1098±337 mg/mmol in
hypertensive patients and from 151±48 to 1179±0.343 mg/mmol in
normotensive subjects (or expressed as THF protein excretion rates from
1.18±0.5 to 6.92±2.12 µg/min in hypertensive patients and from
0.95±0.30 to 7.43±2.16 µg/min in normotensive subjects), provides
evidence that the appearance of the 90-kd peak after exercise
represents this mucoprotein (Fig 4). Statistical
analysis shows that the THF excretion rate at 45 minutes is
significantly different between hypertensive patients and normotensive
subjects (P<.05). The identity of the THF protein was
confirmed by SDS-PAGE and Western blot analysis using
immunochemical detection with a THF protein–specific monoclonal
antibody (Elias) (data not shown).
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Immunohistochemistry
Immunohistochemical analysis of the expression of the small
heparan sulfate proteoglycan in the kidney in different diseases but
also in hypertensive patients is currently under study and will be
published in detail later. However, preliminary data clearly show that
the expression of this heparan sulfate proteoglycan, which is localized
in the glomerular basement membrane and, to a lesser extent, in the
tubular basement membrane but also in the mesangium, is greatly reduced
in hypertensive patients compared with normotensive subjects (Fig 5). In hypertensive patients, the
content of heparan sulfate proteoglycan is reduced in the glomerular
basement membrane but also in the mesangium. Table 5
gives the clinical data of the patients.
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Comparison of Heparan Sulfate Proteoglycans From Human Kidney and
Urine
Heparan sulfate proteoglycan, isolated from human kidney by
several chromatographic steps, and a sample of urine (which was
concentrated but not purified further) were submitted to SDS-PAGE on an
8% to 25% gradient gel and subsequently blotted onto a positively
charged nylon membrane. Immunochemical detection was performed with the
heparan sulfate proteoglycan–specific monoclonal antibody 1F10/B8. Fig 6 clearly shows that the molecular weight distribution
of heparan sulfate proteoglycan from urine is comparable to that from
human kidney, with an Mr of 160 to 30 kd. In
contrast, the small heparan sulfate proteoglycan from aorta has an
Mr distribution of >200 to 80 kd (data not
shown).
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Discussion |
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Heparan sulfate proteoglycans are major components of the glomerular basement membranes and are essential for maintenance of their selective permeability.1 2 Loss of the anionic sites provided by the heparan sulfate proteoglycans is associated with proteinuria and has been observed in a number of nephropathies.3 4 5 6 7 Such a loss might occur as the result of reduced synthesis, enhanced turnover, or degradation of heparan sulfate proteoglycans. However, the exact mechanism of this process is not well understood.
Different types of heparan sulfate proteoglycan have been described in basement membranes,1 2 16 17 18 but the involvement of these different heparan sulfate proteoglycans, and especially of the novel small heparan sulfate proteoglycan, in glomerular selective permeability, stability, and integrity has not yet been clarified.
The aim of the present study was to analyze whether changes in the structure and function of glomerular basement membranes can be detected directly by measurement of the excretion of a component of this basement membrane, eg, heparan sulfate proteoglycan into urine.
This study shows that light to moderate short-term exercise, which
induces only moderate changes in the excretion rates of 1
microglobulin and albumin, causes a 10-fold increase in the urinary
excretion rate of the small heparan sulfate proteoglycan in
normotensive controls (Fig 2, top). The relative increase of the
excretion of heparan sulfate proteoglycan was much stronger (up to
100-fold) compared with individual basal values (Fig 2, bottom). This
was due to the relative broad range of individual heparan sulfate
proteoglycan excretion rates. The time course of this increase clearly
indicates that the increase is not due to de novo synthesis of heparan
sulfate proteoglycan. On the other hand, the selective permeability of
the intact glomerular basement membrane effectively prevents the
excretion of highly negatively charged molecules such as heparan
sulfate proteoglycan from the aorta with an Mr
distribution of >200 to 80 kd.1 Therefore, the excreted
heparan sulfate proteoglycan in normotensive subjects is most likely
released from the glomerular basement membrane and not from other
sources, eg, other basement membranes such as the aortal basement
membrane. This is also supported by the comparable size of the heparan
sulfate proteoglycan from kidney and the excreted heparan sulfate
proteoglycan (Mr, 160 to 30 kd), which is
clearly distinct from that of the human aorta (Fig 6).
Several authors have reported postexercise proteinuria.19 20 21 22 23 But the underlying mechanism of exercise-induced urinary excretion of basement membrane–associated small heparan sulfate proteoglycan has not been clarified. Increased glomerular filtration and saturation of the tubular reabsorption process have been postulated to explain the enhanced excretion of proteins into urine after physical exercise.19 20 The aim of the exercise protocol applied in our study was to compare the increase in urinary protein excretion in normotensive and hypertensive subjects induced by moderate physical exercise at comparable blood pressure levels. Although proteinuria (>200 µg/min) is induced only after strenuous exercise, our results show a significant increase in urinary albumin and THF excretion within the limits of physiological proteinuria, indicating that not only strenuous exercise has an impact on changes in urinary protein excretion.
In addition to changes at the glomerular level, only strenuous exercise
has been reported to influence tubular reabsorption.24 The
fact that urinary 1 microglobulin excretion in our study remained
nearly constant may indicate no influence on tubular reabsorption after
moderate exercise. However, in contrast to Lynn et al,25
we found a significant increase in THF protein excretion, which is
assumed to stem from the plasma membrane of luminal cells of the
ascending limb of the distal convoluted tubule.26 Even
though the function of THF protein is currently not known, these
findings might also indicate exercise-induced changes in tubuli.
Furthermore, the present study shows that light to moderate short-term exercise causes a significantly diminished urinary excretion of the small heparan sulfate proteoglycan in treated hypertensive patients compared with healthy control subjects. A detailed immunohistochemical analysis of the expression of the small heparan sulfate proteoglycan in the kidney for different diseases but also in hypertensive patients is currently underway. However, preliminary data clearly show that the expression of this heparan sulfate proteoglycan, which is localized in the glomerular basement membrane and, to a lesser extent, in the basement membranes of tubuli but also in the mesangium, is greatly reduced in hypertensive patients compared with normotensive subjects (Fig 5). Therefore, the present study provides evidence that the reduction of the exercise-induced urinary glomerular heparan sulfate proteoglycan excretion rate in hypertensive patients not only is due to an impaired turnover of basement membrane heparan sulfate proteoglycan but also might reflect changes in the structure and organization of the glomerular basement membrane in hypertension. It has to be clarified whether the decreased content of heparan sulfate proteoglycan is accompanied by changes of other components of the basement membrane such as laminin, fibronectin, or collagen type IV. Our findings that the exercise-induced increase in the albumin excretion rate is higher in normotensive subjects than in hypertensive patients and that hypertensive patients are not albuminuric continuously suggest that additional changes in the glomerular basement membrane may occur.
Differences in blood pressure might influence glomerular function. Therefore, to avoid large differences in blood pressure compared with the control group, only treated hypertensive patients whose blood pressure was within normal limits were admitted to the study. The urinary excretion of proteins is closely related to the intensity of the workload rather than to the duration of exercise.24 An exercise protocol incorporating an age- and body surface–adjusted workload can be performed even in untrained hypertensive patients. Nevertheless, the control group showed a lower level of blood pressure values without a significant difference in increase of blood pressure under exercise. However, in the normotensive group, the rise in the heparan sulfate proteoglycan excretion rate and ratio was significantly higher than in the hypertensive patients who showed higher blood pressures. Thus, our data indicate that the urinary heparan sulfate proteoglycan excretion rate can be induced by exercise but seems to be independent of the height of the blood pressure increase under physical exercise. Whether antihypertensive treatment may influence the heparan sulfate proteoglycan excretion ratio, as has been proposed for microalbuminuria,27 has to be clarified.
An important novel finding of this study is the pronounced increase in urinary excretion of the small basement membrane–associated heparan sulfate proteoglycan after light to moderate short-term exercise. This increased excretion, which probably reflects an increased turnover of heparan sulfate proteoglycan, will lead to a temporary partial depletion of the glomerular basement membranes. The loss of anionic sites provided by heparan sulfate proteoglycans might be responsible for exercise-induced proteinuria. Even though the molecular mechanism of the release of heparan sulfate proteoglycan from basement membranes remains to be clarified, studies in the rat indicate that heparan sulfate proteoglycan from the glomerular basement membrane exhibits a very rapid turnover, with half-lives in the range of 5 to 20 hours, when examined by metabolic labeling and immunoprecipitation.8 9 10 Whether other components of basement membranes, eg, collagen type IV, laminin, or fibronectin, exhibit a similar increased turnover after exercise remains to be clarified. In the rat, however, half-lives of about 110 days have been found for glomerular basement membrane collagens.28
A second important finding of this study is the significant difference in exercise-induced excretion of the small basement membrane heparan sulfate proteoglycan between hypertensive patients and normotensive subjects, which probably reflects differences in the turnover of heparan sulfate proteoglycan. Our data suggest that the reduced excretion of heparan sulfate proteoglycan is due to changes in the structure and function of glomerular basement membranes in hypertension. This is supported by the decreased content of the small heparan sulfate proteoglycan in glomerular basement membranes of hypertensive patients as shown by immunohistochemistry, even though functional and immunohistochemical data were not from the same patients. Whether basement membranes from other organs or blood vessels are also affected and whether these changes are the result of hypertension or contribute to the pathogenesis of this disease must be analyzed. However, our data indicate that determination of exercise-induced urinary excretion of the novel small heparan sulfate proteoglycan may be a helpful tool in detecting altered glomerular basement membrane function in hypertension or other kidney diseases.
Received June 7, 1993; first decision June 29, 1993; accepted November 1, 1994.
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