Departments of 1 Pharmacology and 4 Molecular Biomedicine, Centro de Investigacion y de Estudios Avanzados del Insituto Politécnico Nacional, and 3 Unidad de Investigacion Medica en Enfermedades Oncologicas, Centro Medico Nacional Siglo XXI, Mexico City CP07300; and 2 Department of Physiology and Pharmacology, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City CP07000, Mexico
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ABSTRACT |
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We have shown increased cyclooxygenase-2 (COX-2) expression in rats with kidney failure. Increased angiotensin II concentration, hypertension, and renal mass reduction have been described during development of kidney failure. Thus we explored each of these mechanisms, because any one of them could be responsible for COX-2 induction. Kidney failure increased systolic blood pressure from 104 ± 5 to 138 ± 2 mmHg, urinary PGE2 from 74 ± 17 to 185 ± 25 ng/24 h, and COX-2 expression from 0.06 ± 0.04 to 0.17 ± 0.03 arbitraty units (AU). Treatment of the rats with ramipril or losartan prevented the increase in blood pressure, urinary PGE2, and COX-2 expression in the rats with kidney failure. Infusion of angiotensin II increased blood pressure from 101 ± 6 to 132 ± 6 mmHg, urinary PGE2 excretion from 62 ± 15 to 155 ± 17 ng/24 h, and COX-2 expression from 0.23 ± 0.01 to 1.6 ± 0.3 AU. When the angiotensin II-infused rats were treated with nitrendipine, blood pressure decreased from 132 ± 6 to 115 ± 2 mmHg, and urinary PGE2 excretion decreased from 152 ± 18 to 97 ± 12 ng/24 h, whereas COX-2 expression was 1.6 ± 0.7 and 1.7 ± 0.5 AU for rats with and without nitrendipine. Blood pressure of the rats with renal pole resection was similar to that in sham rats (97 ± 7 and 91 ± 4 mmHg, respectively), whereas COX-2 expression was increased in rats with renal pole resection, from 0.06 ± 0.04 to 0.12 ± 0.03 AU. We suggest that in kidney failure, the increase in angiotensin II concentration regulates COX-2 expression, thereby increasing prostaglandin synthesis, which contributes to the development of kidney failure.
prostaglandins; renal ablation
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INTRODUCTION |
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IT HAS BEEN SUGGESTED THAT an increase in renal prostaglandin (PG) production may mediate alterations in renal function after renal damage (24). Indeed, increased urinary PGE2 excretion has been reported in chronic or acute renal ablation (19), and inhibition of renal production of PGs in uremic rabbits (14) and glycerol-induced acute kidney failure (25) have been shown to compromise renal blood flow. This suggests that, after renal damage, there is increased production of vasodilator PGs associated with renal vasodilatation (16), impaired autoregulation (4), and increased activity of the renin-angiotensin system (18).
Increased phospholipase A2 (PLA2) activity associated with increased arachidonic acid release has been suggested to be the mechanism responsible for the increased PG production by renal tissue during the development of renal damage (31). Recently, however, we and others have suggested that augmented PG renal excretion after renal ablation (21, 29) or hydronephrotic kidney (23) may be the result of induced cyclooxygenase-2 (COX-2) mRNA expression. Thus the question arises as to which of these or what else is the endogenous inducer of COX-2 mRNA expression during the development of kidney damage. Important intrarenal changes have been described in the model of kidney failure after renal ablation, such as an increase in ANG II concentration, reduction in renal mass with increased sodium delivery to the remnant nephron, and hypertension (11). Any of the renal mechanisms described above could be responsible for COX-2 mRNA regulation. Indeed, increased COX-2 expression was shown in arteries from hypertensive rats (10). A direct effect of ANG II on the regulation of COX-2 was described in cultured vascular smooth muscle cells (17). Finally, a recent study has shown that a high-sodium diet increases COX-2 expression in the renal medulla (32).
These data support the hypothesis that either ANG II, hypertension, or increased sodium delivery in the renal tissue could be responsible for the regulation of COX-2 expression. Thus in the present study, we proposed to investigate the intrarenal mechanism responsible for the regulation of expression of COX-2 mRNA during the development of kidney failure after renal infarction. Therefore, we tested the participation of ANG II, renal mass reduction, or increased blood pressure by dissecting the participation of each of these components, using an antagonist of ANG II, antihypertensive treatment, chronic infusion of ANG II, or an experimental model of renal mass reduction without an increase in blood pressure.
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MATERIALS AND METHODS |
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Experiments were performed in male Wistar rats weighing
250-300 g. Induction of kidney failure was performed as described by inducing renal infarction by arterial ligation (21).
For renal mass reduction by pole resection, the right kidney was
completely removed, and the left kidney underwent surgical resection of
the renal poles. Thus we used rats with 5/6 renal ablation with
infarction (rats with kidney failure) and rats with 5/6 renal ablation
without infarction (rats with renal pole resection). Sham-operated rats were used as controls. For chronic ANG II infusion, Alzet miniosmotic pumps (model 2001, Alzet, Palo Alto, CA) with a capacity of 200 ± 10 µl and an infusion rate of 1.0 ± 0.15 µl/h were filled
with ANG II (Sigma, St. Louis, MO) to obtain an infusion rate of 200 ng · kg1 · min
1. Seven days
after surgery or minipump implantation, development of kidney failure
was evaluated by measuring blood pressure and urinary excretion of
protein, sodium, water, and PGE2 as previously described
(21).
Experimental design.
Four sets of studies were performed in separate sets of rats to study
the role of the ANG II system (group 1), ANG II (group 2), blood pressure (group 3), and mass reduction
(group 4) on the expression of COX-2 mRNA. Group
1 rats were divided into sham-operated, renal infarction, renal
infarction plus losartan (Merck Sharp & Dhome; 1 mg · kg1 · day
1), and renal
infarction plus ramipril (Aventis; 1.5 mg · kg
1 · day
1) groups.
Group 2 rats were divided into sham-operated, renal infarction, and chronic infusion with ANG II groups. Group 3 rats were divided into sham-operated, renal infarction, chronic
infusion with ANG II, and chronic infusion with ANG II plus
nitrendipine (1 mg · kg
1 · day
1) groups.
Group 4 rats were divided into sham-operated, renal infarction, and pole resection groups.
RNA isolation and RT-PCR. Seven days after renal arterial ligation, pole resection, or minipump implantation, urinary PGE2 excretion was measured, renal tissue was obtained, and total RNA was isolated, of which 2 µg were converted to cDNA. COX-2 products were visualized and analyzed as described (21).
Immunohistochemistry. Seven days after renal arterial ligation, pole resection, or minipump implantation, renal tissue was obtained to perform immunohistochemistry or in situ RT-PCR. Under deep anesthesia, rats were exsanguinated, and the kidneys were fixed and embedded in paraffin. Longitudinal 3-µm sections were cut and mounted on glass slides. After deparaffinization, COX-2 was immunodetected as described (1). COX-2 primary monoclonal antibody (1:50; Cayman Chemical, Ann Arbor, MI) was used, and the immunohistochemical reaction was performed according to the streptavidin-biotin-peroxidase technique by using a Super Sensitive Detection Kit (BioGenex).
In situ RT-PCR. Longitudinal 3-µm sections were obtained as described above. The deparaffinized sections were digested with proteinase K. Genomic DNA was digested overnight, and cDNA was generated and underwent amplification using the Super Script One-Step RT-PCR System as described (6). The primers for COX-2 were chosen according to a previous publication (21). To detect the amplified PCR products, we used digoxigenin-labeled 11-dUTP (Roche) that was directly added to the RT-PCR system, and the amplified products were subsequently detected colormetrically.
Statistics. All results are expressed as means ± SE. Multiple comparisons were done by one-way ANOVA. Differences were analyzed using Student's t-test or Dunnett's test. Differences were significant when P < 0.05.
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RESULTS |
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As depicted in Table 1 and as we
have previously shown (21), when we compared sham-operated
rats with rats with renal infarction by arterial ligation, we
demonstrated increased blood pressure, marked proteinuria, and a rise
in urine volume and urinary sodium excretion 1 wk after the renal
infarction. Thus if the data from the sham-operated rats in
groups 1-4 (Table 1) and rats with kidney
failure in groups 1-4 (Npx in Table 1) are
pooled, blood pressure increased from 104 ± 5 to 138 ± 2 mmHg (n = 20) (P < 0.05), urinary
protein increased from 21 ± 4 to 68 ± 9 mg/day (n = 20) (P < 0.05), urinary volume
increased from 15 ± 1 to 33 ± 1 ml/day (n = 20) (P < 0.05), and urinary sodium excretion increased from 1.6 ± 0.1 to 2.9 ± 0.1 meq/day (n = 20) (P < 0.05) in sham rats vs. rats with kidney
failure, respectively.
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Effect of inhibition of ANG II system on renal PG synthesis.
To explore the participation of the ANG II system on COX-2 mRNA
induction, rats were treated with two different antihypertensive drugs:
ramipril, which decreases ANG II synthesis by inhibition of the
angiotensin-converting enzyme, and losartan, which prevents the effects
of ANG II by blocking AT1, the ANG II receptor. Both ramipril and losartan prevented the renal infarction-induced increase in blood pressure, urinary volume, urinary sodium excretion, and urinary protein excretion (Table 1, group 1). Furthermore,
treatment of the rats with either ramipril or losartan prevented the
increase in urinary PGE2 excretion and induction of the
expression of COX-2 mRNA (Fig. 1,
A and B).
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Effect of ANG II infusion on renal PG synthesis.
To evaluate whether high ANG II levels were responsible for induction
of COX-2 mRNA expression, we chronically infused rats with a dose of
200 ng · kg1 · min
1 of ANG
II. Comparison of the hemodynamic and renal effects produced by chronic
infusion of ANG II with the effects produced by sham operation or renal
infarction showed that ANG II increased blood pressure, urinary volume,
urinary protein, and urinary sodium excretion to levels similar to the
effects produced by renal infarction (Table 1, group 2).
Furthermore, chronic infusion of ANG II increased urinary
PGE2 excretion and expression of renal COX-2 mRNA to levels similar to those in rats with renal infarction (Fig.
2, A and B).
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Effect of antihypertensive treatment on renal PG synthesis.
To establish whether the effect of ANG II on PGE2 synthesis
and COX-2 expression was dependent on the hypertensive or
nonhypertensive effects of ANG II, we prevented the ANG II hypertensive
effects by blocking the development of hypertension in the ANG
II-infused rats by treating them with the antihypertensive drug
nitrendipine, which produces vasodilatation by blocking
Ca2+ channels. Treatment with nitrendipine prevented the
increase in blood pressure, urinary volume, urinary protein, and
urinary sodium excretion produced by the chronic infusion of ANG II
(Table 1, group 3). Thus nitrendipine inhibited by 22 ± 3, 37 ± 2, 21 ± 7, and 41 ± 2%, respectively, the
increment of blood pressure, urinary protein, urinary volume, and
urinary sodium excretion produced by the chronic infusion of ANG II.
Inhibition of the increased urinary PGE2 excretion induced
by ANG II infusion was also observed by the treatment of the rats with
nitrendipine (Fig. 3A).
However, reduction of the ANG II-induced increase in blood pressure by
nitrendipine did not affect the induction of expression of renal COX-2
mRNA produced by ANG II (Fig. 3B).
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Effect of renal mass reduction on renal PG synthesis. Finally, to explore the relevance of renal mass reduction on the induction of COX-2 mRNA expression, we used a model of renal mass reduction by surgical resection of the renal poles. This model was not associated with hypertension or increased ANG II levels (9) as was the model of renal infarction.
Comparison of the hemodynamic and renal effects produced by renal ablation by resection of the renal poles with the effects produced by sham operation or renal infarction showed that resection of the renal poles was not associated with an increase in blood pressure or urinary protein excretion, whereas urinary volume and urinary sodium excretion were increased to levels similar to those in the rats with renal infarction (Table 1, group 4). Urinary PGE2 excretion was not affected by renal pole resection, whereas urinary PGE2 excretion was increased by renal infarction (Fig. 4A). Furthermore, expression of renal COX-2 mRNA was not affected by resection of the renal poles and was increased by renal infarction (Fig. 4B).
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COX-2 immunohistochemistry and renal in situ RT-PCR.
Positive COX-2 immunostaining was observed in the renal tissue of rats
with kidney failure after renal infarction (Fig.
5A2). COX-2 cells were
localized in the epithelium of the cortical thick ascending limb of
Henle's loop. Notably, less immunostaining was observed in the
renal tissue of either sham-operated (Fig. 5A1) or rats with
kidney failure that were treated with losartan (Fig. 5A3).
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DISCUSSION |
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In the present study, we investigated the role of ANG II, hypertension, and renal mass reduction in renal COX-2 upregulation. COX-2 expression increased in rats with kidney failure. Angiotensin-converting enzyme inhibition or AT1 receptor blockade prevented the increase in COX-2 expression in rats with kidney failure. ANG II infusion increased COX-2 expression, and this effect was not prevented by lowering the blood pressure with a calcium channel blocker. Surgical resection of five-sixths of the renal mass increased COX-2 expression; however, the magnitude of this effect was lower than the effect of kidney failure. Our data agree with the observations of Wang et. al. (29), who have reported increased glomerular PGE2 related to an increase in COX-2 expression in renal ablation. The pathophysiological significance of these increases in COX-2 and PGE2 synthesis is supported by several studies that have mentioned that PGs may play a role in modulating the renal changes after renal disease. (19, 20, 27) Furthermore, our laboratory previously provided evidence that specific inhibition of COX-2 is associated with amelioration of increased production of PGs and renal damage in kidney failure (21). This observation has been further supported by the report that selective COX-2 inhibition decreases proteinuria and renal sclerosis during renal injury (28). Therefore, these data support the hypothesis that proinflammatory PGs are formed as a consequence of COX-2 induction at the site of renal injury and that these PGs would contribute to the pathophysiology in kidney failure.
ANG II is known to stimulate the production of PGs in vascular smooth muscle cells (5), mesangial cells (22), or endothelial cells (8), likely through the release of arachidonic acid from membrane phospholipid by the activation of a calcium-dependent phospholipase (33). We explored the role of ANG II in the regulation of expression of COX-2 mRNA and increased PGE2 urinary excretion in rats with kidney failure by testing the hypothesis that either inhibition of the angiotensin-converting enzyme or AT1 receptor blockade could prevent the increased expression of COX-2 mRNA and urinary PGE2 excretion seen in the rats with kidney failure. Indeed, treatment of the rats with either ramipril or losartan prevented the effect of kidney failure on the expression of COX-2 mRNA and urinary PGE2 excretion, suggesting that ANG II could be responsible for the regulation of COX-2. However, prevention of the ANG II system also prevented the increase in blood pressure and the renal damage in rats with kidney failure. Thus our data suggested that ANG II directly, or indirectly through hypertension, was responsible for increased expression of COX-2 mRNA in kidney failure. The possible role of hypertension as an inducer of the expression of COX-2 mRNA is supported by previous reports showing that mechanical stimulation increases COX activity (26) and mRNA expression (2) and that hypertension is associated with increased PGI2 and COX-2 expression (10). Therefore, we used a high-ANG II-concentration model through chronic infusion of ANG II and prevented hypertension with the vasodilator nitrendipine. We demonstrated that chronic ANG II infusion was associated with increased urinary PGE2 excretion, renal COX-2 immunoreactivity, and increased expression of COX-2 mRNA and that lowering of blood pressure did not affect the increased expression of COX-2 mRNA produced by chronic ANG II infusion, suggesting that hypertension was not participating in the regulation of COX-2 mRNA expression during the development of kidney failure. However, lowering of blood pressure with nitrendipine was associated with reduction in the ANG II-induced increment in urinary PGE2 excretion. This inhibitory effect of the calcium channel blocker on PGE2 synthesis could be related to inhibition of PLA2, a calcium-dependent enzyme (15). Our hypothesis of a nonhypertensive effect of ANG II on the regulation of mRNA expression is supported by Alexander et. al. (3), who recently reported that chronic ANG II infusion is associated with a significant elevation of preproendothelin mRNA through a mechanism unrelated to hypertension. Several authors have reported a direct effect of ANG II on mRNA expression in cultured aortic smooth cells (7), myocytes (13), and mesangial cells (12); the latter study reported that ANG II-dependent mRNA regulation was associated with promoter activity modulation by signaling pathways that include calcium, protein kinase C, and tyrosine kinase (12). Furthermore, a recent study demonstrated that ANG II regulates COX-2 and PG synthesis through p42/44 and p38 mitogen-activated protein kinase pathways in rat vascular smooth muscle cells (17). Thus these reports further support our hypothesis that ANG II can directly modulate COX-2 expression during the development of kidney failure.
Next, we evaluated whether the reduction of renal mass associated with rats with kidney failure could be involved in the regulation of the COX-2 mRNA expression. Therefore, to differentiate the effect of renal mass reduction from that of ANG II, we used a model of renal mass reduction that was not associated with an increase in ANG II or hypertension (9).
Our results demonstrated that reduction of renal mass by renal pole resection was not associated with an increase in blood pressure and/or changes in urinary PGE2 excretion and that expression of COX-2 mRNA was increased compared with sham rats. However, the increase in COX-2 expression was lower than in the rats with kidney failure, suggesting that renal mass reduction may be an alternative mechanism responsible for the regulation of the expression of COX-2 mRNA during the development of kidney failure. There are two possible mechanisms in the rats with renal pole resection that could be inducing the expression of COX-2 mRNA. First, given that there are increased macrophages and other inflammatory cells in the remnant kidney (29), it is possible that a component of the small increment of expression of COX-2 mRNA in renal mass reduction by surgical ablation compared with the sham-operated rats was secondary to infiltrating cells. Second, previous observations have shown that expression of COX-2 mRNA varies markedly with the variation of sodium in the diet (32). Although sodium in the diet was not modified in the model of renal pole resection, reduction of total renal mass will change the sodium load-renal mass relationship in these animals, suggesting that indeed the increase in COX-2 expression in rats with renal pole resection may be associated with an increase in sodium delivery to the remnant tissue. However, the question arises as to why, in the rats with renal pole resection, did we not see similar changes in the expression of COX-2 compared with those seen in rats with kidney failure. We suggest that this could be associated with the fact that regulation of expression of COX-2 mRNA by changes in sodium in the diet had directionally opposite effects in the cortex and inner medulla (32). Thus it is possible that by using total renal tissue (cortex and medulla) as the sample in our experiments, differences in the expression of COX-2 mRNA can be attenuated or go unnoticed. Moreover, the effect of sodium in the diet on PG synthesis has been associated with changes in ANG II concentration (30), and in our model of renal poles resection, we did not observe changes in blood pressure, suggesting that there was no significant production of ANG II that could be synergizing the effect of renal mass reduction on COX-2 expression.
We suggest that ANG II, through a direct effect, could be responsible for the regulation of expression of COX-2 during the development of kidney failure.
The findings discussed above suggest a possible mechanism for the greater production of PGE2 in the renal tissue from rats with kidney failure. A greater expression of COX-2 mRNA may account for the increased content of renal COX-2 and higher activity of COX-2 and, thereby, increased production of urinary PGE2.
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ACKNOWLEDGEMENTS |
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We thank Eunice Romo for technical assistance and Dr. Romero Garcia Torres, Nephrology Department, Instituto Nacional de Cardiologia, Mexico, for the interpretation of tissue slides.
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FOOTNOTES |
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This work was supported by Mexican Council of Science and Technology (CONACYT) Grant 31048.
Address for reprint requests and other correspondence: B. Escalante, Dept. of Molecular Biomedicine, Centro de Investigacion y de Estudios Avanzados del IPN, Avenida Instituto Politecnico Nacional 2508, Mexico City, CP 07300 Mexico (E-mail: bescalan{at}mail.cinvestav.mx).
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.
10.1152/ajprenal.00194.2001
Received 26 June 2001; accepted in final form 29 October 2001.
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