Telmisartan inhibits both oxidative stress and renal fibrosis after unilateral ureteral obstruction in acatalasemic mice

Sugiyama, Hiroshi; Kobayashi, Mizuho; Wang, Da Hong; Sunami, Reiko; Maeshima, Yohei; Yamasaki, Yasushi; Masuoka, Noriyoshi; Kira, Shohei; Makino, Hírofumi

doi:10.1093/ndt/gfi045

Cited by 78 publications

(80 citation statements)

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“…32 In this study, the mRNA expression of NADPH oxidase subunits such as p47phox, p40phox, p67phox, p22phox and gp91phox was increased in the UUO kidney compared with the sham-operated kidney. 33 Consistent with these findings, superoxide anion generation in the renal interstitium was increased as evaluated by DHE staining. Rho-kinase inhibitor or ACE inhibitor monotherapy did not attenuate the DHE-positive area or the mRNA expression levels of NADPH oxidase subunits.…”

Section: Discussionsupporting

confidence: 71%

Beneficial effects of a combination of Rho-kinase inhibitor and ACE inhibitor on tubulointerstitial fibrosis induced by unilateral ureteral obstruction

et al. 2010

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We and others recently reported that long-term Rho-kinase inhibition has renoprotective effects. This study was designed to compare the effects of an angiotensin-converting enzyme (ACE) inhibitor (imidapril), a Rho-kinase inhibitor (fasudil) and a combination of them both on renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO). We also attempted to elucidate the mechanism involved. Imidapril (50 mg l -1 ), fasudil (1 g l -1 ) or a combination of them both was given in drinking water to mice, and their effects were compared on renal interstitial fibrosis induced by UUO. We assessed histological findings, monocyte/macrophage infiltration, myofibroblast differentiation, oxidative stress and the expression of various mRNA in the kidney by UUO. Eleven days after UUO, wild-type kidney was characterized by increased fibrotic area, dihydroethidium (DHE)-positive area, a-smooth muscle actin (SMA)-positive area, F4/80-positive area and the increased expression of various mRNA. Fasudil and imidapril similarly improved fibrotic area (À23%, À15%), DHE-positive area (À13%, À11%), a-SMA-positive area (À22%, À15%), F4/80-positive area (À42%, À34%) and the expression of various mRNA, most of which were significant (Po0.05). The combination of imidapril and fasudil further improved fibrotic area (À52%), DHE-positive area (À26%), a-SMApositive area (À33%), F4/80-positive area (À62%) and the expression of various mRNA (all Po0.05 vs. monotherapy). Compared with either agent alone, the combination of an ACE inhibitor and a Rho-kinase inhibitor was more effective for the prevention of renal interstitial fibrosis because of the inhibition of transforming growth factor-b/collagen, monocyte/macrophage infiltration, myofibroblast differentiation, inflammation and the oxidative stress pathway.

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Section: Discussionsupporting

confidence: 71%

Beneficial effects of a combination of Rho-kinase inhibitor and ACE inhibitor on tubulointerstitial fibrosis induced by unilateral ureteral obstruction

et al. 2010

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“…Oxidative stress is coupled to hypertension in several models and demonstrated in kidneys with ureteral obstruction (28), where it might impair renal NO production. Treatment modalities that increase NO formation (40) or inhibit oxidative stress (54) are beneficial to the progression of cellular and molecular parameters of tubulointerstitial fibrosis caused by obstruction of the ureter, whereas NO deficiency increases renal damage (21).…”

Section: Discussionmentioning

confidence: 99%

Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals

Carlström¹,

Brown²,

Edlund³

et al. 2008

American Journal of Physiology-Renal Physiology

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Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals. Am J Physiol Renal Physiol 294: F362-F370, 2008. First published November 21, 2007 doi:10.1152/ajprenal.00410.2007.-Hydronephrotic animals develop renal injury and hypertension, which is associated with an abnormal tubuloglomerular feedback (TGF). The TGF sensitivity is coupled to nitric oxide (NO) in the macula densa. The involvement of reduced NO availability in the development of hypertension in hydronephrosis was investigated. Hydronephrosis was induced by ureteral obstruction in young rats. Blood pressure and renal excretion were measured in adulthood, under different sodium conditions, and before and after chronic administration of either N G -nitro-L-arginine methyl ester (L-NAME) or L-arginine. Blood samples for ADMA, SDMA, and L-arginine analysis were taken and the renal tissue was used for histology and determination of NO synthase (NOS) proteins. TGF characteristics were determined by stop-flow pressure technique before and after administration of 7-nitroindazole (7-NI) or L-arginine. Hydronephrotic animals developed salt-sensitive hypertension, which was associated with pressure natriuresis and diuresis. The blood pressure response to L-NAME was attenuated and L-arginine supplementation decreased blood pressure in hydronephrotic animals, but not in the controls. Under control conditions, reactivity and sensitivity of the TGF response were greater in the hydronephrotic group. 7-NI administration increased TGF reactivity and sensitivity in control animals, whereas, in hydronephrotic animals, neuronal NOS (nNOS) inhibition had no effect. L-Arginine attenuated TGF response more in hydronephrotic kidneys than in controls. The hydronephrotic animals displayed various degrees of histopathological changes. ADMA and SDMA levels were higher and the renal expressions of nNOS and endothelial NOS proteins were lower in animals with hydronephrosis. Reduced NO availability in the diseased kidney in hydronephrosis, and subsequent resetting of the TGF mechanism, plays an important role in the development of hypertension.ADMA; tubuloglomerular feedback; L-arginine; L-NAME; telemetry; blood pressure HYPERTENSION IS THE MOST COMMON chronic disorders worldwide and secondary forms of hypertension are found in 5-10% of the hypertensive population, of which most can be linked to renal disease (24). In humans, as well as in experimental models of salt-sensitive hypertension, there is a growing body of evidence pointing at a close relationship between nitric oxide (NO) deficiency and development of hypertension (37).Hydronephrosis due to obstruction at the level of the pelvicureteric junction is a common condition in children, with an incidence in newborns of ϳ1%. The obstruction is mostly partial and congenital of origin. Unilateral hydronephrosis causes salt-sensitive hypertension in both rats (5) and mice (7).The renal function in hydronephrotic animals, measured as renal blood flow and glomerular filtration rate (GFR), is rather...

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“…It is well known that reactive oxygen species, primarily superoxide, can interact with NO. Oxidative stress has been demonstrated in the hydronephrotic kidney [27][28][29][30][31][32] and could consequently reduce the NO availability and increase the renal vascular tone. Indeed, in the SOD1 transgenic mice, overexpressing CuZnSOD, a strong but similar L-NAMEinduced response (approximately Ϫ40%) was observed for all of the groups, whereas in the SOD1-knockouts, lacking CuZnSOD, there was an abolished L-NAME response in AAs from the hydronephrotic kidney.…”

Section: Discussionmentioning

confidence: 99%

“…It has been demonstrated that reduced NO availability may increase the NOS transcription, 36 and, therefore, one could speculate that the gene expressions of the different NOS isoforms are upregulated to compensate for low NO availability in hydronephrosis. It is likely that oxidative stress [27][28][29][30][31][32] can increase the elimination of NO, 37 increase AA resistance, and contribute to hypertension. 38 This idea was strengthened by the findings in the SOD1 mice.…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Deficiency and Increased Adenosine Response of Afferent Arterioles in Hydronephrotic Mice With Hypertension

et al. 2008

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Abstract-Afferent arterioles were used to investigate the role of adenosine, angiotensin II, NO, and reactive oxygen species in the pathogenesis of increased tubuloglomerular feedback response in hydronephrosis. Hydronephrosis was induced in wild-type mice, superoxide dismutase-1 overexpressed mice (superoxide-dismutase-1 transgenic), and deficient mice (superoxide dismutase-1 knockout). Isotonic contractions in isolated perfused arterioles and mRNA expression of NO synthase isoforms, adenosine, and angiotensin II receptors were measured. In wild-type mice, N G -nitro-L-arginine methyl ester (L-NAME) did not change the basal arteriolar diameter of hydronephrotic kidneys (Ϫ6%) but reduced it in control (Ϫ12%) and contralateral arterioles (Ϫ43%). Angiotensin II mediated a weaker maximum contraction of hydronephrotic arterioles (Ϫ18%) than in control (Ϫ42%) and contralateral arterioles (Ϫ49%). The maximum adenosine-induced constriction was stronger in hydronephrotic (Ϫ19%) compared with control (Ϫ8%) and contralateral kidneys (Ϯ0%). The response to angiotensin II became stronger in the presence of adenosine in hydronephrotic kidneys and attenuated in contralateral arterioles. L-NAME increased angiotensin II responses of all of the groups but less in hydronephrotic kidneys. The mRNA expression of endothelial NO synthase and inducible NO synthase was upregulated in the hydronephrotic arterioles. No differences were found for adenosine or angiotensin II receptors. In superoxide dismutase-1 transgenic mice, strong but similar L-NAME response (Ϫ40%) was observed for all of the groups. This response was totally abolished in arterioles of hydronephrotic superoxide dismutase-1 knockout mice. In conclusion, hydronephrosis is associated with changes in the arteriolar reactivity of both hydronephrotic and contralateral kidneys. Increased oxidative stress, reduced NO availability, and stronger reactivity to adenosine of the hydronephrotic kidney may contribute to the enhanced tubuloglomerular feedback responsiveness in hydronephrosis and be involved in the development of hypertension. Key Words: angiotensin II Ⅲ L-NAME Ⅲ oxidative stress Ⅲ NO synthase Ⅲ superoxide dismutase Ⅲ tubuloglomerular feedback H ydronephrosis because of uretero-pelvic junction obstruction is a common condition in newborns, with an incidence of Ϸ1%. Both rats and mice with hydronephrosis, because of chronic partial ureteral obstruction, develop renal injury 1 and salt-sensitive hypertension 2,3 that can be attenuated by relief of the obstruction. 4 The mechanisms are thought to be associated with increased activity of the renin-angiotensin system, 2 increased oxidative stress, and reduced NO availability in the diseased kidney. 5 In micropuncture studies of hydronephrotic animals, the tubuloglomerular feedback (TGF) has a higher responsiveness in the hydronephrotic kidney. 5,6 An increased TGF response, as seen in hydronephrotic kidneys, has also been described in spontaneously hypertensive rats, 7 Milan hypertensive rats 8 during development of hyperte...

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Telmisartan inhibits both oxidative stress and renal fibrosis after unilateral ureteral obstruction in acatalasemic mice

Abstract: The AT1 receptor antagonist telmisartan ameliorated renal fibrosis after UUO by inhibition of oxidative stress, even under acatalasemic conditions.

Cited by 78 publications

References 19 publications

Beneficial effects of a combination of Rho-kinase inhibitor and ACE inhibitor on tubulointerstitial fibrosis induced by unilateral ureteral obstruction

Beneficial effects of a combination of Rho-kinase inhibitor and ACE inhibitor on tubulointerstitial fibrosis induced by unilateral ureteral obstruction

Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals

Nitric Oxide Deficiency and Increased Adenosine Response of Afferent Arterioles in Hydronephrotic Mice With Hypertension

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