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*
Department of Nephrology, Instituto Nacional de
Cardiología, Mexico City, Mexico
Division of Nephrology, University of Washington Medical Center, Seattle,
Washington
Instituto de Investigaciones Biomédicas,
Maracaibo, Venezuela.
Address correspondence to Dr. Martha Franco, Nephrology Department, Instituto Nacional de Cardiología, Juan Badiano No. 1, Mexico City, Tlalpan 14080, Mexico. Phone: 525-573-6902; Fax: 525-573-7716; E-mail: marthafranco{at}eudoramail.com
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Lombardi et al. (3) reported that salt-sensitive hypertension develops in rats after the transient administration of angiotensin II (AngII). Histologic analysis at the end of the AngII infusion showed focal arteriolar lesions and minimal glomerular changes; in contrast, the primary abnormality consisted of focal tubulointerstitial injury. Salt-sensitive hypertension also is present in other conditions associated with microvascular and tubulointerstitial injury, such as after exposure to catecholamines or cyclosporine (4,5). It was hypothesized that the enhanced sodium reabsorption observed in these conditions may result from local generation of vasoactive mediators in ischemic areas at sites of tubulointerstitial injury; in addition, peritubular capillary rarefaction observed in these models theoretically might shift the pressure natriuresis curve (5).
Because histologic injury occurs primarily in tubulointerstitial areas, the contribution of glomerular abnormalities to salt sensitivity is thought to be relatively minor. It is well established, however, that some of the determinants of GFR can exert a profound influence on the pressure natriuresis relationship. For example, a rise in afferent resistance and a decrease in the ultrafiltration coefficient (Kf) will limit the filtered load and shift the pressure natriuresis curve to the right (6). These glomerular functional changes could be mediated by locally released vasoactive mediators or by afferent arteriolar disease without altering glomerular histology (7). One important component of tubulointerstitial injury associated with salt-sensitive hypertension is infiltration of mononuclear cells mediated by chemokines and leukocyte adhesion proteins expressed by injured renal cells. Infiltrating cells that produce cytokines and vasoactive factors in situ (8) could influence glomerular hemodynamics, shifting the pressure natriuresis curve to the right, and thereby contribute to the pathogenesis of salt-sensitive hypertension.
We recently examined the role of infiltrating mononuclear cells in this model by administering the immunosuppressive agent mycophenolate mofetil (MMF) during the AngII infusion (9). Although MMF had a minimal effect on the acute effects of AngII to increase BP, the MMF-treated rats did not show the increase in BP during the subsequent exposure to a high-salt diet (HSD). This protection was associated with a reduction of T-cell infiltration, less tubulointerstitial injury, and a reduction in the number of tubulointerstitial cells expressing AngII (9).
This study was designed to evaluate the role of glomerular hemodynamics and its relationship to the associated inflammatory process in the development of salt-sensitive hypertension. For this purpose, micropuncture studies were performed at different stages during the development of salt-sensitive hypertension after transient exposure to AngII. In addition, we examined rats that were treated with AngII and MMF in which salt sensitivity did not develop.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BP Measurements
Systolic BP (SBP) measurements were performed in conscious, restrained rats
by tail-cuff plethysmography (Narco Biosystems, Austin, TX). Rats were
conditioned twice before the BP was measured at basal period, every week
during the first 2 wk and every 2 wk for the rest of the study.
Other Measurements
Rats were placed in metabolic cages with water and food ad
libitum, and urine was collected for a 24-h period; the collections were
taken in a basal period and at days 14, 26, and 49 of the study, before the
micropuncture experiments. The samples were used for determination of
proteinuria and nitrites/nitrates. Urinary protein was measured by the
trichloracetic acid assay, using bovine serum albumin as the protein standard
(11). Urinary
NO2- and NO3- were generated in
the urine samples obtained during the sampling period. Samples were incubated
with Escherichia coli nitrate reductase to convert the
NO3- to NO2-, as described by
Bartholomew (12) and Granger
et al. (13). To
prepare this enzyme, we grew E. coli for 18 h under anaerobic
conditions in a nitrate-rich medium, washed, resuspended in phosphate-buffered
saline, and frozen at -70°C until use. The samples were incubated with the
enzyme in phosphate-ammonium formate buffer (pH 7.3) for 1 h at 37°C.
After incubation, total NO2- in the samples
(representing both NO2- and reduced
NO3-) was measured using the Griess reagent. Known
concentrations of NaNO2 and NaNO3 were used as standards
in each assay.
Micropuncture Experiments
For micropuncture studies, the rats were anesthetized with sodium
pentobarbital (30 mg/kg intraperitoneally), and supplementary doses were
instilled as required. The rats were placed on a thermoregulated table, and
the temperature was maintained at 37°C. Polyethylene tubing was used to
catheterize the trachea (PE-240), both jugular veins and femoral arteries
(PE-50), and the left ureter (PE-10). The left kidney was exposed, placed in a
lucite holder, sealed, and covered with Ringer's solution. Mean arterial BP
(MAP) was monitored continuously with a pressure transducer (Model p23 LX;
Gould, Hato Rey, Puerto Rico) and recorded on a polygraph (Grass Instruments,
Quincy MA). Blood samples were taken periodically every 45 to 60 min and
replaced with blood from a normal donor rat.
Rats were maintained euvolemic by infusion of 10 ml/kg body wt of isotonic rat plasma during surgery, followed by an infusion of 10% polyfructosan (Inutest; Laevosan-Gesellschafft, Linz, Austria) and 0.9% sodium saline solution, as vehicle, at the rate of 2.5 ml/h. After 60 min, seven timed samples of proximal tubular fluid were obtained to determine flow rate and polyfructosan concentration; intratubular hydrostatic pressure under free flow and stop-flow conditions and peritubular capillary pressures (PTCP) were measured in other proximal tubules with a servo-null device (Servo-Nulling Pressure System, Instrumentation for Physiology and Medicine, Inc., San Diego, CA) as described previously (14). Polyfructosan was measured in plasma samples. Glomerular colloid osmotic pressure was estimated in protein from blood taken from the femoral artery and surface efferent arterioles.
Polyfructosan concentrations were determined by the technique of Davidson and Sackner (15). The volume of fluid collected from an individual proximal tubule was estimated from the length of the column of fluid in a capillary tube of uniform bore and known internal diameter. The concentration of tubular polyfructosan was measured by the method of Vurek and Pegram (16). The protein concentration in the efferent samples was determined by the method of Viets et al. (17).
Proximal single-nephron GFR (SNGFR), intratubular pressure during free-flow
conditions and under stopped-flow conditions after blocking the tubular lumen
with a long oil column(SFP), glomerular capillary hydrostatic pressure
(PGC), PTCP, afferent oncotic pressure(
A), efferent oncotic
pressure (E), PGC gradient (
P), single-nephron
filtration fraction, single-nephron glomerular plasma flow (GPF), afferent
(RA) and efferent (RE) resistances, ultrafiltration
coefficient (Kf), and oncotic pressure were calculated according to
equations given elsewhere
(18). We estimated
PGC by the stopped-flow method according to the following equation:
PGC = SFP + A. As this method for measuring SFP requires
blockade of the tubuloglomerular feedback mechanism (TGF), the estimated
PGC may be slightly overestimated; however, this has not been
substantiated in rats (19) and
also is the method that is generally accepted for studying rats that lack
superficial glomeruli
(18).
Histologic Analysis and Morphometry
Tissue was fixed in methylcarnoys, processed and embedded in paraffin,
sectioned (4 µm), and stained by periodic acid-Schiff reagent. Afferent
arterioles were identified by their location adjacent to the vascular pole of
the glomerular tuft, by the presence of an elastic lamina, and by having fewer
endothelial cells than the efferent arteriole. Arteriolar measurements were
performed blinded at 100 x oil using computer image analysis (Optimas,
Silver Spring, MD). Afferent and efferent arteriolar wall thickness was
quantified in individual arterioles by measuring the width of arteriole wall
(exclusive of the endothelium), using the mean of the thinnest and thickest
segments. At least 7 to 20 arterioles were examined per biopsy.
Statistical Analyses
Groups were evaluated by one-way ANOVA followed by a Tukey posttest.
Statistical significance was defined at P < 0.05. Results in
tables and figures are expressed as mean ± SEM.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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P > E;
Table 1), it was possible to
calculate the Kf, the product of the capillary permeability and
filtration area, which was found to be reduced by 44%
(Table 1). A marked decrease of
two of the determinants of GFR (GPF and Kf) resulted in a 35% fall
of SNGFR (Figure 3B) despite
the concomitant rise in glomerular capillary pressure
(Figure 2C). In relation to the
peritubular capillary circulation, a significant increase in PTCP was observed
despite the reduction in glomerular flow, indicating an increase in resistance
to flow in the renal medulla (Table
1).
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Glomerular Hemodynamics during AngII Infusion in MMF-Treated
Rats
During the AngII infusion, MMF-treated rats demonstrated a similar
elevation of SBP as well as a fall in urinary nitrates compared with rats that
received AngII alone (Figure 1, A and
C). Urinary protein excretion, however, was significantly reduced
(Figure 1B). MMF treatment did
not prevent the acute hemodynamic changes associated with AngII infusion and
was associated with an equivalent fall in GFR
(Table 1) and a similar degree
of cortical vasoconstriction as reflected by increased RA and
RE. Changes in GPF, SNGFR, and PGC also were not
different between the AngII and AngII/MMF groups (Figures
2 and
3 and
Table 1).
Post-AngII Glomerular Hemodynamics
Post-AngII infusion renal hemodynamic findings are shown in
Table 1 and Figures
2 and
3. The withdrawal of the AngII
infusion was followed by a sharp fall in SBP to near-normal values (185.2
± 3.9 to 143.5 ± 2.8 mmHg; P < 0.001). However, the
subsequent administration of an HSD during the following 5 wk resulted in a
progressive rise in SBP (153.9 ± 4.3 and 162.2 ± 4.5 mmHg at 1
and 5 wk of HSD; P < 0.001), demonstrating the development of salt
sensitivity (Figure 1A). During
the phase of salt-sensitive hypertension, urine protein excretion and urinary
excretion of NO2-/NO3- returned to
normal values and remained unchanged despite the observed rise in SBP during
this period (Figure 1, B and
C). Total GFR after 1 and 5 wk of HSD returned to values similar
to their respective sham-operated controls and was no longer different from
HSD control rats (Table 1). The
most striking functional change associated with the development of
salt-sensitive hypertension was the persistence of cortical vasoconstriction.
RA and RE remained elevated, and GPF was equally reduced
at 1 and 5 wk after implementation of the HSD (Figures
2, A and B, and
3A). After the AngII infusion
was stopped, the PGC decreased and was no longer different from
sham-operated rats on an HSD (Table
1) Kf values continued to be lower than their
respective controls, and the difference was significant at 5 wk
(Table 1). SNGFR continued to
be 26% lower than controls Figure
3B).
Glomerular Hemodynamics after AngII/MMF Treatment
The rats of the AngII+MMF group experienced a reduction in BP similar to
the AngII group after withdrawal of AngII
(Figure 1A). However, in marked
contrast to rats that were administered AngII alone, SBP did not rise during
the subsequent 5 wk of HSD; thus, salt sensitivity was prevented. Similar to
rats that were administered AngII alone, there was a recovery in the total GFR
at both 1 and 5 wk such that there was no difference compared with
time-matched HSD controls (Table
1). In contrast to rats that were administered AngII alone,
AngII+MMF-treated rats were largely protected from the post-AngII cortical
vasoconstriction. RA remained slightly but significantly elevated
compared with the time-matched HSD controls but was 30% lower compared with
rats that had received AngII alone (Figure
2). RE also was 20% lower than AngII rats and was not
different from HSD controls (Figure
2). GPF, SNGFR, and Kf progressively recovered,
reaching normal values at week 5 (Figure
3 and Table 1).
In summary, our results suggest that there is a close association between cortical vasoconstriction and the development of salt-sensitive hypertension. This was supported further by the finding of a significant inverse correlation between GPF and the corresponding SBP of AngII, AngII+MMF, and sham-operated rats at 5 wk of the HSD (Figure 4).
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Histologic Correlations
Renal tissue obtained at the end of the AngII infusion (2 wk) showed
afferent arteriolar thickening with rare areas of fibrinoid necrosis. Most
glomeruli appeared normal. The most evident injury was in the
tubulointerstitium, with focal areas of tubular dilation and atrophy, often
accompanied by interstitial expansion and mononuclear cell infiltration
(Figure 5). Renal tissue also
was examined at 1 and 5 wk after the AngII had been withdrawn. The afferent
arterioles appeared hypertrophic, and glomeruli were normal. Focal
tubulointerstitial injury remained but in general was less severe in
comparison with the histology at the end of the AngII infusion. MMF treatment
was associated with a modest improvement in the tubulointerstitial disease,
both at the end of the AngII infusion and at later points, as was reported
previously (Figure 5)
(9).
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Measurements of the afferent arteriolar wall thickness were made and are shown in Table 2. The infusion of AngII was associated with a 33% increase in afferent arteriolar wall thickness at 2 wk compared with normal baseline controls (P < 0.001). The afferent arteriolar wall thickness persisted in the post-AngII infusion period (HDS 1 and HDS 5 wk) and was significantly greater than control rats that were administered an HSD for a similar period (Table 2 and Figure 6; P < 0.001). MMF treatment did not prevent the afferent arteriolar thickening at the end of the AngII infusion. However, the afferent arteriolar thickening at 5 wk of the HSD had normalized in the rats that had received AngII and MMF and was significantly less than that observed in rats that were treated with AngII alone (Table 2).
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In contrast to the changes observed in the afferent arterioles, no significant changes were observed with the efferent arterioles (Table 2).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study, we evaluated the pathogenic role of the glomerular microcirculatory changes during the development of salt-sensitive hypertension after transient exposure to AngII. As previously observed in this model, SBP increased throughout the 14-d infusion period (3) and was associated with marked proteinuria and a dramatic fall in urinary nitrate excretion.
At the end of the AngII infusion period, glomerular hemodynamics were characterized by intense cortical vasoconstriction, with high RA and RE and a fall in GPF and Kf. The SNGFR was reduced out of proportion as a result of a concomitant decrease of Kf. This hemodynamic pattern is similar to the changes induced by acute infusion of the peptide (20). A fall in the production of renal vasodilators such as nitric oxide, as suggested by the marked decrease in urinary nitrites/nitrates during the AngII infusion, also might contribute to the renal vasoconstriction. Consistent with the reduction in urinary nitrites, we previously reported that the infusion of AngII at the dose used in this study results in a reduction in immunostaining of nitric oxide synthase 1 (NOS I) in the macula densa and of NOS III in the outer and inner medulla (3).
The withdrawal of AngII was followed by a significant fall in BP. However, when the rats were then placed on an HSD, a progressive elevation of BP occurred for the remaining 5 wk of the study, confirming our previous observations (3) that transient exposure to AngII results in the development of salt sensitivity. An important observation was that the glomerular microcirculatory changes observed during the acute infusion period persisted up to 5 wk after the AngII withdrawal. The principal findings were a persistent increase in RA and RE, a reduction in plasma flow and SNGFR, and a lower Kf. The observation that the reduction in SNGFR was disproportionate to total GFR suggests a compensation by juxtamedullary nephrons, which autoregulate less well and hence might be filtering more because of the elevation in systemic BP.
A shift of the pressure natriuresis curve to the right can result from enhanced tubular sodium resorption, increased RA or reduced glomerular filtration (6). In this study, the last two of these factors were found to be altered, indicating a major contribution of glomerular function in limiting sodium excretion.
We also performed micropuncture studies in rats that received both AngII and MMF. We previously reported that MMF treatment during the period that rats are receiving AngII will prevent the development of post-AngII salt-sensitive hypertension (9). Thus, it was of interest to compare the glomerular hemodynamics of this group to angiotensin alone, as both groups were exposed to the same dose of AngII and the same diet.
MMF did not prevent the increase in systemic or glomerular pressure or the degree of renal vasoconstriction induced during the AngII infusion. Indeed, the only difference between AngII-infused rats and AngII/MMF-treated rats during the AngII infusion was that there was less urinary protein excretion in the latter group. The proteinuria induced by AngII has been attributed to the rise in glomerular pressure and changes in glomerular capillary wall permeability. As MMF-treated rats showed similar SBP and glomerular pressure, this suggests that MMF may have had direct or indirect effects on the increased permeability induced by AngII.
One of the most interesting findings was that rats that were treated with AngII and MMF failed to show salt-sensitive increases in BP in the post-AngII period, and this was paralleled by an improvement in the hemodynamic alterations. Specifically, although some increase in RA remained, there was a marked improvement in other parameters, with RE, GPF, Kf, and SNGFR all returning to levels no different from HSD sham controls. In addition, a significant negative correlation was observed between GPF and SBP after 5 wk on HSD, providing strong evidence that the persistent renal vasoconstriction is a critical factor in the salt sensitivity in this model.
Several mechanisms may contribute to the increased RA and RE and altered glomerular hemodynamics in the post-AngII period. First, although glomeruli appeared normal, there were persistent structural changes involving the afferent arteriole. Specifically, there was an increase in afferent arteriolar wall thickness observed both at the end of the AngII infusion and in the post-AngII period. The increase in afferent arteriolar wall thickness likely was a consequence of pressor-induced hypertrophy or direct hypertrophic effects of AngII on vascular smooth muscle cells (21,22). The arteriolar hypertrophy may contribute to increased RA as a consequence of either a greater vasoconstrictive response to stimuli or an encroachment of the lumen secondary to the medial hypertrophy. The importance of the arteriolar lesion in modulating the glomerular hemodynamics was supported by the studies in which MMF was administered. In these rats, the afferent arteriolar thickening resolved during the post-AngII period and at 5 wk was no different from HSD-alone controls.
The observation that the glomerular hemodynamic pattern observed during and after AngII infusion was the same also suggests that there may be some continued exposure to AngII. In this regard, Zhou et al. (23,24) demonstrated that the infusion of AngII results in both the accumulation of exogenous AngII and local generation of AngII. However, the observation that rats that were treated with AngII and MMF failed to develop salt sensitivity after the AngII infusion makes it less likely that accumulation of exogenous AngII is responsible for the alterations in post-AngII glomerular hemodynamics.
Recently, our group reported that the tubulointerstitial injury that occurs secondary to AngII is associated with an increase in expression in angiotensin-converting enzyme both in the proximal tubular brush border and at sites of interstitial injury (7). Furthermore, we recently identified mononuclear cells expressing AngII at the sites of interstitial injury and found that the infiltration of these AngII-positive cells is reduced by MMF treatment (9). Thus, it is possible that locally generated AngII by infiltrating inflammatory cells could mediate renal vasoconstriction and hence affect glomerular hemodynamics by direct effects on renal microvasculature structure and function. These findings suggest that the inflammatory process in the interstitium may play a pivotal role in the pathogenesis of this form of salt-sensitive hypertension by maintaining glomerular microcirculatory abnormalities.
In addition, persistent vasoconstriction could result from the local generation of other vasoconstrictive factors or the loss of vasodilatory factors. For example, AngII infusion increases renal endothelin-1 content, decreases neuronal NOS I in the macula densa, and decreases NOS III in the renal medulla (3). We also noted a decrease in urinary nitrite excretion during the AngII infusion in this study. However, the excretion of nitrates returned to control values at the end of the study and recovery of medullary endothelial NOS expression also occurs (data not shown). Nevertheless, it is possible that the observed intrarenal NO production, although normal under baseline conditions, represents an impaired response in the presence of AngII-driven hemodynamic changes that are present during this phase of the experiments. If such is the case, then insufficient NO production could contribute to the afferent arteriole vasoconstriction and/or directly affect tubular sodium excretion (25).
In summary, rats that are administered AngII for 2 wk develop salt-sensitive hypertension. The post-AngII—induced hypertension was associated with persistent afferent and efferent arteriolar vasoconstriction and a reduction in GPF, SNGFR, and Kf. Renal histology documented persistent afferent arteriolar wall thickening and mild tubulointerstitial injury in these animals. Treatment with MMF was associated with a similar elevation of BP during the AngII infusion but prevented the subsequent development of salt sensitivity in association with normalization of the hemodynamic and structural changes. These studies suggest that persistent alterations in glomerular hemodynamics, perhaps induced by structural and functional changes in the microvasculature and tubulointerstitium, may be responsible for the development of salt-sensitive hypertension after exposure to AngII.
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Acknowledgments |
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V. Alvarez, Y. Quiroz, M. Nava, H. Pons, and B. Rodriguez-Iturbe Overload proteinuria is followed by salt-sensitive hypertension caused by renal infiltration of immune cells Am J Physiol Renal Physiol, November 1, 2002; 283(5): F1132 - F1141. [Abstract] [Full Text] [PDF]
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R. J. Johnson, J. Herrera-Acosta, G. F. Schreiner, and B. Rodriguez-Iturbe Subtle Acquired Renal Injury as a Mechanism of Salt-Sensitive Hypertension N. Engl. J. Med., March 21, 2002; 346(12): 913 - 923. [Full Text] [PDF]
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B. Rodriguez-Iturbe, Y. Quiroz, M. Nava, L. Bonet, M. Chavez, J. Herrera-Acosta, R. J. Johnson, and H. A. Pons Reduction of renal immune cell infiltration results in blood pressure control in genetically hypertensive rats Am J Physiol Renal Physiol, |
, sham rats; [UNK], AngII-treated rats;
, AngII+mycophenolate mofetil (MMF)-treated rats. a = P <
0.05 versus day 0; b = P < 0.05 AngII versus
AngII+MMF; c = P < 0.05 versus before HSD. Values are
mean ± SEM.
); rats after 2 wk of AngII, rats on HSD for 1 wk
after receiving AngII during 2 wk, and rats on HSD for 5 wk after receiving
AngII during 2 wk (
); sham-operated rats on HSD for 1 wk and 5 wk
([UNK]). Rats after 2 wk of AngII that received MMF, rats on HSD for 1 wk
after receiving AngII and MMF during 2 wk, and rats on HSD for 5 wk after
receiving AngII and MMF during 2 wk ([UNK]). a = P < 0.05
versus controls; b = P < 0.05 AngII versus
AngII+MMF.
), and sham-operated rats (
