Departments of 1 Nephrology and 2 Pathology, Instituto Nacional de Cardiologia I Chavez, 14080 Mexico City, Mexico; 3 Division of Nephrology, Baylor College of Medicine, Houston, Texas 77030; and 4 Hospital Universitario and Universidad del Zulia, Maracaibo, Venezuela
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ABSTRACT |
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Mildly hyperuricemic rats
develop renin-dependent hypertension and interstitial renal disease.
Hyperuricemia might also induce changes in glomerular hemodynamics.
Micropuncture experiments under deep anesthesia were performed in
Sprague-Dawley rats fed a low-salt diet (LS group), fed a low-salt diet
and treated with oxonic acid (OA/LS group), and fed a low-salt diet and
treated with oxonic acid + allopurinol (OA/LS/AP group) for 5 wk.
The OA/LS group developed hyperuricemia and hypertension compared with
the LS group: 3.1 ± 0.2 vs. 1.1 ± 0.2 mg/dl
(P < 0.01) and 143 ± 4 vs. 126 ± 2 mmHg
(P < 0.01). Hyperuricemic rats developed increased
glomerular capillary pressure compared with the LS rats: 56.7 ± 1.2 vs. 51.9 ± 1.4 mmHg (P < 0.05). Pre- and
postglomerular resistances were not increased. Histology showed
afferent arteriolar thickening with increased -smooth muscle actin
staining of the media. Allopurinol prevented hyperuricemia (1.14 ± 0.2 mg/dl), systemic (121.8 ± 2.8 mmHg) and glomerular
hypertension (50.1 ± 0.8 mmHg), and arteriolopathy in oxonic
acid-treated rats. Linear regression analysis showed that glomerular
capillary pressure and arteriolar thickening correlated positively with
serum uric acid and systolic blood pressure. Glomerular hypertension
may be partially mediated by an abnormal vascular response to systemic hypertension due to arteriolopathy of the afferent arteriole.
uric acid; arteriolopathy; renal hemodynamics; micropuncture; hypertension
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INTRODUCTION |
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CONTROVERSY EXISTS over the role of hyperuricemia in renal disease (16). For example, gout can be associated with a renal lesion ("gouty nephropathy") characterized by glomerulosclerosis, interstitial fibrosis, and arteriolosclerosis, often with focal urate deposits in the interstitium (30). However, many patients with longstanding gout have hypertension and/or are older, and the renal injury is also compatible with hypertensive or aging-related renal injury (2, 23). A syndrome of familiar juvenile hyperuricemia has also been described with similar histological features, except urate deposition appears to be rare; debate over the role of uric acid in the renal injury in this condition has also raged (6). Hyperuricemia has also been reported to be a risk factor for progression, although the mechanism by which uric acid may accelerate renal disease is unknown. For example, in a recent study of 6,403 subjects, serum uric acid was found to be an independent risk factor for development of renal insufficiency and carried a greater risk than proteinuria (14).
Recently, a model of mild hyperuricemia was reported in rats by inhibiting uricase with oxonic acid (19, 20). Rats fed low doses of oxonic acid develop an up to threefold increase in serum uric acid without intrarenal crystal deposition. Rats developed hypertension, afferent arteriolar thickening, and mild renal interstitial fibrosis, with interstitial collagen deposition and macrophage infiltration (19, 20). These effects were most pronounced if the rats were fed a low-sodium diet (19, 20). Because a mild increment of serum uric acid was associated with hypertension and arteriolopathy of preglomerular vessels, the present study was performed to determine the glomerular hemodynamics in this model.
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METHODS |
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Experimental design.
All animal procedures were approved by the Animal Care Committee. Male
Sprague-Dawley rats (150-250 g) were used in all experiments, and
blood pressure and serum uric acid were measured at 2 and 5 wk. To
produce hyperuricemia, 2% oxonic acid (Sigma, St. Louis, MO) mixed in
a low-sodium diet (0.125% NaCl; Ziegler, Gardner, PA) was administered
to the rats (OA/LS group). To distinguish the effects of hyperuricemia
from those of oxonic acid, a group of rats received allopurinol (Sigma;
150 mg/l drinking water), an inhibitor of xanthine oxidase, which is
the enzyme responsible for uric acid synthesis, to prevent the rise in
uric acid induced by oxonic acid (OA/LS/AP group). We studied the
following groups: low-sodium diet alone (LS group, n = 8), OA/LS group (n = 9), and OA/LS/AP group
(n = 8). Micropuncture studies were performed at 5 wk.
Animals were anesthetized with pentobarbital sodium (30 mg/kg ip) and
placed on a thermoregulated table to maintain body temperature at
37°C. Trachea, jugular veins, femoral arteries, and the left ureter
were catheterized with polyethylene tubing (PE-240, PE-50, and PE-10).
The left kidney was exposed, placed in a Lucite holder, sealed with
agar, and covered with Ringer solution. Mean arterial pressure (MAP)
was monitored with a pressure transducer (model p23db, Gould, San Juan,
PR) and recorded on a polygraph (Grass Instruments, Quincy, MA). Blood
was sampled periodically and replaced with blood from a donor rat. Rats
were maintained under euvolemic conditions by infusion of isotonic rat
plasma (10 ml/kg body wt) during surgery, followed by an infusion of
25% polyfructosan at 2.2 ml/h (Inutest, Laevosan-Gesellschaft, Linz,
Austria). After 60 min, five to six 3-min collection samples of
proximal tubular fluid were obtained to determine flow rate and
polyfructosan concentration. Intratubular pressure under free-flow and
stop-flow conditions and peritubular capillary pressure were measured
in other proximal tubules with a servo-null device (Servo Nulling
Pressure System, Instrumentation for Physiology and Medicine, San
Diego, CA). Polyfructosan was measured in plasma samples. Glomerular
colloid osmotic pressure was estimated in protein from blood of the
femoral artery and surface efferent arterioles. Polyfructosan concentrations were determined by the technique of Davidson and Sackner
(7). Tubular fluid volume was estimated as previously described (11). Concentration of tubular polyfructosan was
measured by the method of Vurek and Pegram (33). Protein
concentration in afferent and efferent samples was determined according
to the method of Viets et al. (32). MAP, glomerular
filtration rate (GFR), single-nephron GFR (SNGFR), proximal tubular
pressure, glomerular capillary hydrostatic pressure (PGC),
transcapillary hydrostatic pressure gradient (P), single-nephron
plasma flow (
A), afferent (RA) and
efferent (RE) resistances, and filtration coefficient
(Kf) were calculated according to equations
given elsewhere (11).
Evaluation. In all studies, systolic blood pressure (SBP) was measured by tail-cuff sphygmomanometer using an automated system (Narco Biosystems, Houston, TX). All animals were preconditioned for blood pressure measurements 1 wk before each experiment. Serum uric acid was measured by the colorimetric uricase method using a commercial kit (King Diagnostics).
Renal histology.
Renal biopsies were fixed in methyl-Carnoy's solution and embedded in
paraffin. Sections (4 µm) of tissue fixed in methyl-Carnoy's solution were stained with periodic acid-Schiff reagent. Arteriolar morphology was assessed in five rats of each group by indirect peroxidase immunostaining for -smooth muscle actin (DAKO,
Carpinteria, CA) (20).
Quantification of morphology.
Quantifications were performed blinded. Only vessels adjacent to
glomeruli in the outer cortex were selected. Afferent arterioles were
distinguished from efferent arterioles by the presence of an internal
elastic lamina and by thin, flattened endothelial cells
(19). With the use of immersion-fixed tissue, afferent arteriolar wall thickness was measured by computer image analysis. For
each arteriole, the outline of the vessel and its internal lumen
(excluding the endothelium) was generated using computer analysis to
calculate the total medial area (outline inline) in 10 arterioles per biopsy. Vessels that were cross sectioned or not
sectioned transversally, providing an asymmetrical wall, were excluded
from the present study. The media-to-lumen ratio was calculated by the
outline-inline relationship (19).
Statistical analysis. Values are means ± SE. Differences between groups were evaluated by ANOVA with appropriate correction for multiple comparisons (Bonferroni's correction). The relationship between variables was assessed by linear regression analysis.
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RESULTS |
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General features of the model.
Consistent with previous reports (20), mild hyperuricemia
was observed in OA/LS rats compared with the LS group
(P < 0.05; Table 1) in
association with development of modest hypertension noted by
intra-arterial and tail-cuff measurements [MAP (P < 0.05; Table 1) and SBP (P < 0.01; Table
2)]. The hyperuricemia and elevation in
blood pressure were prevented in the OA/LS/AP group. A significant
positive linear regression between serum uric acid levels and SBP was
found (r2 = 0.49, P < 0.0001). Although body weight at 5 wk was significantly higher in the
OA/LS/AP group than in the other groups, the overall weight gain was
not different among the groups, indicating similar nutritional
conditions (data not shown).
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Glomerular hemodynamics.
Using micropuncture techniques, we examined the effect of hyperuricemia
on glomerular hemodynamics. Table 1 depicts values obtained during
micropuncture studies. The mean value for PGC was increased
in OA/LS rats to 56.7 ± 1.2 mmHg, a value significantly greater
than that observed in the LS group (51.9 ± 1.4 mmHg,
P < 0.05) and decreased in the OA/LS/AP group to
values similar to those in LS rats (50.1 ± 0.8 mmHg,
P < 0.01). A significant positive linear regression
was observed between serum uric acid and PGC
(r2 = 0.34, P = 0.003; Fig.
1). PGC also correlated with
SBP (r2 = 0.33, P = 0.003;
Fig. 2) and MAP
(r2 = 0.3, P = 0.005).
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Histological studies.
Histological findings are shown in Table 2 and Figs.
3 and 4.
As we reported previously, there were no significant changes in
glomerular or tubulointerstitial structures by routine light microscopy; however, immunostaining for -smooth muscle actin demonstrated hypertrophy of preglomerular vessels in the OA/LS group.
Arteriolar thickening was totally prevented in the OA/LS/AP rats
(P < 0.01; Table 2). A significant positive
correlation was found between arteriolar area and SBP
(r2 = 0.53, P = 0.002),
serum uric acid (r2 = 0.44, P = 0.008), and PGC
(r2 = 0.32, P = 0.028; Fig.
4). Arteriolar media-to-lumen ratio was also increased in OA/LS animals
compared with the LS group (P < 0.01; Table 2). An
increase in the arteriolar media-to-lumen ratio was prevented in
OA/LS/AP animals (P < 0.01; Table 2).
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DISCUSSION |
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In this study, we have examined the effect of mild hyperuricemia on glomerular hemodynamics in the rat. The primary new finding is that hyperuricemia in the OA/LS model is associated with glomerular hypertension. Within individual rats, there was a striking correlation between serum uric acid and glomerular hydrostatic pressure. Evidence that this effect was due to uric acid and not oxonic acid was provided by including the group that received allopurinol. This group maintained normal uric acid levels, despite receiving oxonic acid, and showed no increase in PGC. It is possible that part of the beneficial effect exerted by allopurinol may be attributed to its antioxidant properties. Allopurinol, by blocking xanthine oxidase, will reduce superoxide anion and uric acid production by this enzymatic pathway. However, in the kidney, expression of xanthine oxidase is limited (26, 35), and it has a minimum participation during oxidative stress induced by ischemia-reperfusion (8, 15). Moreover, the oxidative stress induced by angiotensin II is mediated by NADP/NADPH oxidase (10), which should not be affected by allopurinol. Finally, in previous reports, our laboratory showed that the prevention of hyperuricemia using a uricosuric agent (benzodiarone) avoided the rise in arterial pressure and afferent arteriolopathy in this model (19). The observation that lowering uric acid by two different ways controlled blood pressure and arteriolopathy in oxonic acid-treated rats provides strong evidence that these effects are mediated by uric acid independent of oxidative stress.
The normal response to an increase in MAP is afferent arteriolar vasoconstriction, which is an autoregulatory mechanism that acts to prevent the transmission of the increased pressure to the glomerular circulation. Afferent arteriolar vasoconstriction tended to be higher in the OA/LS group, but it was not significantly different from the LS or OA/LS/AP groups.
The reason for a rise of RA in hyperuricemic rats that is
insufficient to prevent transmission of increased pressure to the glomeruli may relate to the afferent arteriolopathy that occurs in this
model (19). The arteriolopathy was characterized in this
study by increased arteriolar thickness and media-to-lumen ratio with
increased -smooth muscle actin staining. It has been previously
reported to develop independently of blood pressure, although it is
dependent on the renin-angiotensin system (19). It may
also be mediated by direct effects of uric acid on vascular smooth
muscle cells (19, 27). Interestingly, there was a
significant correlation between arteriolar thickening and glomerular
pressure. One may speculate that arteriolar disease may have
contributed to the transmission of SBP, because proliferation of
vascular smooth muscle cells and increased collagen deposition in the
vascular wall might be expected to increase rigidity of the vascular
wall and thus limit its capacity to contract in response to higher perfusion pressure.
An intriguing finding was that the increased glomerular pressure in
hyperuricemic rats was not associated with a simultaneous rise in
single-nephron filtration rate, since the other determinants of GFR,
a and Kf, were not changed.
This finding could be explained by a concomitant rise in proximal
tubular pressure, which offset the elevation of PGC and
maintained the
P. There is no apparent explanation for the rise in
intratubular pressure; one possibility, however, is that higher plasma
levels of uric acid may induce the formation of intratubular urate
crystals, which could produce a mild tubular obstruction. In this
regard, histological analysis did not demonstrate urate deposition or
tubular dilatation. Independently of the mechanism responsible for the
rise in intratubular pressure, we do not believe that tubular
obstruction could explain the rise in glomerular pressure. In previous
studies evaluating the effect of ureteral obstruction on glomerular
hemodynamics, glomerular pressure was elevated transiently after
complete ureteral obstruction but returned to normal values after
24 h (34); in studies with partial ureteral
obstruction, glomerular pressure was unchanged (4).
Moreover, in the only study in which glomerular hemodynamics and
tubuloglomerular feedback (TGF) were determined in rats with chronic
partial ureteral obstruction, PGC was unchanged, and the activity of the TGF mechanism was increased. Such an increase in TGF
activity would result in vasoconstriction of preglomerular vessels,
which would reduce SNGFR (22).
Increased glomerular pressure is known to precede and is thought to be partially responsible for late development of hypertrophy and sclerosis in other experimental models, such as subtotal renal ablation. PGC was slightly lower in our hyperuricemic rats than in rats 4-6 wk after five-sixths nephrectomy: 56.7 vs. 60 mmHg (1, 5, 13, 17, 18). However, the rise of PGC in hyperuricemic rats probably reflects a more significant dysfunction of preglomerular vessels, because after renal ablation, blood pressure is higher (170-190 mmHg), renal mass is reduced, and there is a significant degree of afferent dysfunction; in contrast, in hyperuricemic rats, hypertension is less severe and the nephron population remains intact.
These studies were performed under low-salt dietary conditions. In this
dietary condition, hyperuricemia had the most prominent effects on
blood pressure and renal injury (19); therefore, we were
most interested in the glomerular hemodynamic changes in this
condition. However, it is known that a low-salt diet alone results in
some alterations in glomerular hemodynamics compared with a normal-salt
diet (11, 31). Salt depletion alone induced a slight
elevation of MAP, a lower total GFR, and a lower SNGFR (11,
31). The effect of salt depletion on SNGFR is due to decrements
in Kf and A, despite higher
PGC and
P. In the present study, these changes were
particularly accentuated in the LS group compared with other studies
(3, 28) and likely relate to the more prolonged period of
salt depletion in the present study (5 vs. 2 wk) and, potentially,
greater activation of the renin-angiotensin system. Calculated
RA and RE in the LS group also showed a
vasoconstrictor effect and were higher than reported for rats fed a
normal-salt diet (11, 31) or fed a low-salt diet for a
shorter period of time (3, 28). Although the low-salt diet
does alter glomerular hemodynamics, the comparison between groups
remains valid.
Whether hyperuricemia also increases glomerular pressure under normal- or high-salt dietary conditions was not addressed in this study. However, previous studies in hyperuricemic rats fed a normal-salt diet have documented increased systemic pressures, increased renin expression, and development of an afferent arteriolopathy (19, 20), so it is likely that similar changes in glomerular hemodynamic changes may occur.
The importance of these findings in relation to human disease is uncertain. One must be careful in extrapolating from animal models to human disease. Nevertheless, chronic hyperuricemia has been associated with renal disease in patients with gout (9, 25, 30) and has been used to predict progression in IgA nephropathy (24, 29) and development of renal insufficiency in the normal population (14). Hyperuricemia has also been reported to accelerate experimental cyclosporin nephropathy (21).
In summary, hyperuricemic rats fed a low-salt diet develop glomerular hypertension, which appears to be due to insufficient vasoconstriction of the afferent arteriole. We postulate that this may be due to development of an arteriolopathy that may alter the response of preglomerular vessels, thus allowing the transmission of systemic pressure to the glomerular capillary tuft. Because hyperuricemia is a common and easily treatable condition, it is important to clarify whether there is a pathogenic role for uric acid in renal disease.
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ACKNOWLEDGEMENTS |
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Support for this study was provided by Consejo Nacional de Ciencia y Tecnología (Mexico City, Mexico) Unrestricted Grant 37275-M and National Heart, Lung, and Blood Institute Grant HL-68607.
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FOOTNOTES |
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Address for reprint requests and other correspondence: L. G. Sánchez-Lozada, Dept. of Nephrology, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, 14080 Mexico City, Mexico (E-mail: lgsanchezlozada{at}hotmail.com).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
June 26, 2002;10.1152/ajprenal.00170.2002
Received 1 May 2002; accepted in final form 12 June 2002.
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