Losartan modulation on NOS isoforms and COX-2 expression in early renal fibrogenesis in unilateral obstruction

Manucha, Walter; Oliveros, Liliana; Carrizo, Liliana; Seltzer, Alicia; Vallés, Patricia G.

doi:10.1111/j.1523-1755.2004.00643.x

Cited by 59 publications

(40 citation statements)

References 53 publications

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“…2) Losartan treatment reduced the increased COX-2 protein and mRNA expressions and the increased release of PGF 2␣ and 8-isoprostane found in aortic segments from SHR, without further effects by the COX-2 inhibitor NS-398 in this release. In this line of evidence, losartan treatment is reported to decrease the increased inducible nitric-oxide synthase and COX-2 expression observed after experimental renal interstitial fibrosis (Manucha et al, 2004). However, the AT 1 receptor blocker candesartan has also been reported to increase the renocortical COX-2 mRNA expression in 5-week-old SHR, but it has no effect in older rats (Hocherl et al, 2001).…”

Section: At 1 Receptors and Cox-2 In Hypertension 385mentioning

confidence: 83%

Losartan Reduces the Increased Participation of Cyclooxygenase-2-Derived Products in Vascular Responses of Hypertensive Rats

Álvarez

Pérez-Girón²,

Hernanz³

et al. 2007

J Pharmacol Exp Ther

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This study analyzes the role of angiotensin II (Ang II), via AT 1 receptors, in the involvement of cyclooxygenase (COX)-2-derived prostanoids in phenylephrine responses in normotensive rats (Wistar Kyoto; WKY) and spontaneously hypertensive rats (SHR). Aorta from rats untreated or treated for 12 weeks with losartan (15 mg/kg ⅐ day) or hydralazine plus hydrochlorothiazide (44 and 9.4 mg/kg ⅐ day, respectively) and vascular smooth muscle cells (VSMC) from SHR were used. Vascular reactivity was analyzed by isometric recording; COX-2 expression by Western blot and reverse transcription-polymerase chain reaction; prostaglandin (PG)I 2 , PGF 2␣ , 8-isoprostane, and total antioxidant status (TAS) by commercial kits; superoxide anion (O 2 . ) by lucigenin chemiluminescence; and plasmatic malondi- . production, and MDA levels were higher in SHR, but TAS was similar in both strains.Losartan, but not hydralazine-hydrochlorothiazide treatment, reduced COX-2 expression and the effect of NS-398 on phenylephrine responses in SHR. Losartan also increased TAS and reduced PGF 2␣ , PGI 2 , 8-isoprostane, and O 2 . production and MDA levels in SHR. Ang II (0.1 M) induced COX-2 expression in VSMC from SHR that was reduced by 30 M apocynin and 100 M allopurinol, NADPH oxidase, and xanthine oxidase inhibitors, respectively. In conclusion, AT 1 receptor activation by Ang II could be involved in the increased participation of COX-2-derived contractile prostanoids in vasoconstriction to phenylephrine with hypertension, probably through COX-2 expression regulation. The increased oxidative stress seems to be one of the mechanisms involved.

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Section: At 1 Receptors and Cox-2 In Hypertension 385mentioning

confidence: 83%

Losartan Reduces the Increased Participation of Cyclooxygenase-2-Derived Products in Vascular Responses of Hypertensive Rats

Álvarez

Pérez-Girón²,

Hernanz³

et al. 2007

J Pharmacol Exp Ther

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“…Following 24-h complete UUO in the adult rat, renal cortical COX-2 decreases, while medullary COX-2 increases (10). In this regard, COX-2 inhibition attenuates progressive renal injury in the adult rat subjected to complete UUO (33), and losartan decreases renal COX-2 expression and reduces fibrosis resulting from UUO (30). Similarly, candesartan reduces renal medullary COX-2 induction and ameliorates renal function following release of bilateral ureteral obstruction in the adult rat (23).…”

Section: Discussionmentioning

confidence: 94%

Angiotensin AT₁-receptor inhibition exacerbates renal injury resulting from partial unilateral ureteral obstruction in the neonatal rat

Coleman¹,

Minor²,

Burt³

et al. 2007

American Journal of Physiology-Renal Physiology

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Coleman CM, Minor JJ, Burt LE, Thornhill BA, Forbes MS, Chevalier RL. Angiotensin AT1-receptor inhibition exacerbates renal injury resulting from partial unilateral ureteral obstruction in the neonatal rat. Am J Physiol Renal Physiol 293: F262-F268, 2007. First published April 18, 2007; doi:10.1152/ajprenal.00071.2007.-The renin-angiotensin system is activated in the developing kidney and is necessary for normal renal development, but is further activated by unilateral ureteral obstruction (UUO). During nephrogenesis, there is a switch from a preponderance of angiotensin AT2 to AT1 receptors in the rat. We examined the renal cellular response to angiotensin II receptor inhibition in the neonatal rat subjected to partial UUO under anesthesia within 48 h of birth. Group I ("early") received saline vehicle, losartan (AT1 inhibitor), or PD-123319 (AT2 inhibitor) during the completion of nephrogenesis in the first 10 days of life. Group II ("late") received each of the three treatments throughout the subsequent 10 days of life. Kidneys were harvested at 21 days, and the distribution of renin, apoptosis, macrophages, ␣-smooth muscle actin, and collagen was determined. Losartan and PD-123319 each increased vascular renin distribution in both kidneys. Partial UUO reduced growth and increased apoptosis, macrophages, ␣-smooth muscle actin, and collagen in the obstructed kidney. Early losartan treatment further increased ␣-smooth muscle actin and collagen in the obstructed kidney and induced apoptosis, macrophages, and collagen in the contralateral kidney. Late losartan treatment had no effect on any of the parameters in either kidney, and PD-123319 had no effect on either kidney. We conclude that selective inhibition of AT1 receptors during nephrogenesis (but not during subsequent renal maturation) exacerbates injury to the obstructed kidney and also injures the contralateral kidney. These results suggest that angiotensin II receptor blockers should be avoided in the developing hydronephrotic kidney.hydronephrosis; nephrogenesis; apoptosis; ␣-smooth muscle actin; collagen CONGENITAL URINARY TRACT OBSTRUCTION is a major cause of chronic renal insufficiency in infants and children (43). Despite intrauterine diagnosis and prompt evaluation and management of the neonate, the combination of fetal urinary tract maldevelopment and the consequences of urinary obstruction on the developing kidney lead to renal injury that is present even at the time of birth. Prevention of progression of renal injury in these infants is even more critical than in older patients with renal disorders.The renin-angiotensin system (RAS) has been shown to play a significant role in the progression of virtually all renal disorders, and pharmacological inhibition of angiotensin II is a widely accepted therapy for attenuating or preventing renal deterioration. Since the RAS is activated to a greater extent neonatally than at older ages, and urinary tract obstruction itself markedly activates the RAS, the rationale for angiotensin II inhibition in this set...

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“…Furthermore, a non-hemodynamic effect of angiotensin II as a profibrotic cytokine, contributing to renal injury, can be included in LP as demonstrated in other experimental models (Klahr et al 1988;Ishidoya et al 1995;Manucha et al 2004). Besides its effect on cell proliferation and growth, angiotensin II has been shown to induce apoptosis (Ding et al 2002).…”

Section: Discussionmentioning

confidence: 97%

“…Evidence involving angiotensin II in altered renal non-hemodynamics, leading to the tubulointerstitial injury, has been reported. For these events, angiotensin II promotes the synthesis of several cytokines and growth factors that contribute to the progression of the renal injury (Kaneto et al 1994;Manucha et al 2004). Moreover, studies have recently shown that angiotensin II can stimulate oxidative stress (Pueyo et al 1998).…”

Section: Introductionmentioning

confidence: 99%

Heat shock protein 70 expression is associated with inhibition of renal tubule epithelial cell apoptosis during recovery from low-protein feeding

Carrizo

Ruete²,

Manucha³

et al. 2006

Cell Stress Chaper

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The cellular stress response can mediate cellular protection through expression of heat shock protein (Hsp70), which can interfere with the process of apoptotic cell death. Factors regulating renal epithelial cell apoptosis include angiotensin II. In the present study, we have examined the relationship between the Hsp70 expression and the apoptotic pathway in the kidneys from low-protein-fed rats (8% protein). The possible cytoprotective role of Hsp70 has been evaluated during low-protein feeding and after reincorporation of 24% protein in the diet. The effect of angiotensin II AT 1 receptor inhibition has also been studied. Rats were fed with a low-protein (LP) diet (8% protein) for 14 days, and then the animals were recovered by means of a normal protein diet (24% protein) (RP) for 14, 21, and 30 days, and control rats received 24% protein (NP) in the diet. LP and NP rats treated with Losartan (10 mg/kg) were also evaluated. The following methods were performed on the kidneys: terminal deoxynucleotidyltransferasemediated dUTP nick end labeling assay for apoptosis, reverse transcriptase-polymerase chain reaction assay for AT 1 , Bax, and Bcl-2 messenger ribonucleic acid (mRNA) expression, and immunohistochemical and Western blot for Hsp70 and caspase 3 protein expression and activity. In the LP group, the cells of the medullary ducts (MDs) showed increased apoptosis associated with weak immunoreaction for Hsp70 and decreased Hsp70 protein levels. In these animals, enhanced proapoptotic ratio Bax/Bcl-2 linked to decreased procaspase 3 protein levels with increased caspase 3 activation were demonstrated. A cytoprotection attributed to Hsp70 could be noted in the RP rats after 21 days of reincorporation of the normal diet, and in the LP-fed group treated with Losartan. In these cases, the MD cells displayed decreased apoptosis and increased Hsp70 expression in colocalization staining, and high Hsp70 levels in cytosolic fraction. A decreased proapoptotic ratio Bax/Bcl-2, associated with increased Bcl-2 mRNA, was also observed. Our results provide evidence for an antiapoptotic, cytoprotective effect of Hsp70 in kidney MD cells of rats with LP intake, when the animals were recovered with 24% protein in diet and after angiotensin II AT 1 receptor inhibition. Angiotensin II seems to play a role in the pathogenesis of tubule epithelial cell apoptosis during LP feeding.

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Losartan modulation on NOS isoforms and COX-2 expression in early renal fibrogenesis in unilateral obstruction

Abstract: These results allowed us to infer an interstitial fibrogenesis prevention independent action of losartan, involving NOS isoforms and COX-2, in unilateral obstructive nephropathy.

Cited by 59 publications

References 53 publications

Losartan Reduces the Increased Participation of Cyclooxygenase-2-Derived Products in Vascular Responses of Hypertensive Rats

Losartan Reduces the Increased Participation of Cyclooxygenase-2-Derived Products in Vascular Responses of Hypertensive Rats

Angiotensin AT₁-receptor inhibition exacerbates renal injury resulting from partial unilateral ureteral obstruction in the neonatal rat

Heat shock protein 70 expression is associated with inhibition of renal tubule epithelial cell apoptosis during recovery from low-protein feeding

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