Activation of the aldosterone/mineralocorticoid receptor system and protective effects of mineralocorticoid receptor antagonism in retinal ischemia-reperfusion injury

Liu, Ye; Hirooka, Kazuyuki; Nishiyama, Akira; Lei, Bai; Nakamura, Takehiro; Itano, Toshifumi; Fujita, Tomoyoshi; Zhang, Jinsong; Shiraga, Fumio

doi:10.1016/j.exer.2011.12.012

Cited by 22 publications

(20 citation statements)

References 26 publications

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“…It has been suggested that the superoxide ions react with NO to produce peroxynitrite, which then causes accentuated lipid peroxidation and protein and deoxyribonucleic acid (DNA) modifications, resulting in cellular damage. Taken together, these results suggest that the iNOS-NO-peroxynitrite -dependent pathway may be one of the mechanisms of I/R-induced lung injury [15]. During intestinal I/R, the level of NO has been shown to be altered.…”

mentioning

confidence: 72%

“…MR antagonists have successfully been used as clinical interventions for the treatment of hypertension, heart failure and post-myocardial infarction remodelling [17,19]. Prophylactic MR antagonism with spironolactone (Sp) in rats has been shown to completely prevent the ischemic injuries of kidney, heart and brain [15,[19][20][21][22]. Several studies have tried t o e l u c i d a t e t h e u n d e r l y i n g m e c h a n i s m o f M R antagonist-induced cardioprotection [23].…”

mentioning

confidence: 99%

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Reduction of Acute Lung Injury by Administration of Spironolactone After Intestinal Ischemia and Reperfusion in Rats

Barut¹,

Özaçmak²,

TURAN³

et al. 2016

CIM

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Purpose: Multiple organ failure, including acute lung injury, is a common complication of intestinal ischemia and reperfusion (I/R) injury and contributes to its high mortality rate. Activated polymorphonuclear neutrophils and reactive oxygen species contribute to the lung injury caused by intestinal I/R. Mineralokortikoid receptor antagonist spironolactone has a protective effect against I/R injury in animal models of retina, kidney, heart, and brain. The aim of the present study is to investigate the effect of aldosteron receptor blocker spironolactone on lung injury induced by intestinal I/R.Methods: Wistar albino rats were divided into four groups: (1) sham control; (2) intestinal I/R (30 min of ischemia by superior mesenteric artery occlusion followed by 3 h of reperfusion); (3) spironolactone pretreatment (20 mg/kg) + I/R; and, (4) spironolactone pretreatment without I/R. Spironolactone was given orally 3 days prior to intestinal I/R. A marker for lipid peroxidation (malondialdehyde; MDA), an indicator or oxidation state (reduced glutathione; GSH), an index of polymorphonuclear neutrophil sequestration (myeloperoxidase; MPO), inducible nitric oxide synthase (iNOS) immunoreactivity, and the histopathology of the lung tissue were analyzed.Results: Spironolactone pretreatment markedly reduced intestinal I/R-induced lung injury as indicated by histology and MDA and MPO levels. Moreover, the pretreatment decreased the iNOS immunoreactivity. Conclusion:The present study strongly suggests that spironolactone pretreatment decreased neutrophil infiltration, iNOS induction, oxidative stress, and histopathological injury in an experimental model of intestinal I/R induced-lung injury of rats.

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confidence: 72%

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confidence: 99%

Reduction of Acute Lung Injury by Administration of Spironolactone After Intestinal Ischemia and Reperfusion in Rats

Barut¹,

Özaçmak²,

TURAN³

et al. 2016

CIM

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“…[18][19][20]22 There have been a substantial number of studies that have examined the mechanisms responsible for retinal ischemia-reperfusion injury. The findings of these studies have demonstrated the involvement of a variety of factors including glutamate, 6,23 free radicals, 24 inflammatory adhesion molecules, 25 nitric oxide, 26 and cytokines.…”

Section: Discussionmentioning

confidence: 99%

“…N-methyl-D-aspartate injury was induced as previously reported. 8 Based on previously reported methodologies, 19 the pupil of the right eye was dilated with tropicamide phenylephrine hydrochloride (Santen Pharmaceuticals Co. Ltd., Osaka, Japan), after which 2 lL of 20 mM NMDA or 2 lL of 80 lg/kg aldosterone was injected into the vitreous body of the right eye using a 32-gauge needle and Hamilton syringe. For the vehicle control, the same volume of PBS was then injected in the left eye.…”

Section: Intravitreal Injection Of Nmda or Aldosteronementioning

confidence: 99%

“…[14][15][16][17] In our previous study, we reported finding that after ischemia-reperfusion there was an increase in the expression of angiotensin II type 1 receptor (AT1-R) in the retina. 18,19 In addition, we also found there were reductions in retinal ischemia-reperfusion injuries after administering treatments that included the mineralocorticoid receptor antagonist, spironolactone, an angiotensin-converting enzyme inhibitor, and an AT1-R blocker.18,20 Furthermore, we also recently reported that the RGC loss associated with the thinning of the retinal nerve fiber layer without elevated IOP that occurs after the systemic administration of aldosterone could be prevented by the administration of spironolactone.21 Thus, the RAAS appears to play an important role with regard to the neuronal degeneration that occurs in the retina.The NMDA receptor-mediated signal is one of the most important pathways involved in the death of RGCs. Therefore, it is important to understand the specific relationship between RAAS and the NMDA receptor-mediated signal.…”

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confidence: 99%

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The Relationship Between the Renin-Angiotensin–Aldosterone System and NMDA Receptor-Mediated Signal and the Prevention of Retinal Ganglion Cell Death

Kobayashi

Hirooka

Ono

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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Citation: Kobayashi M, Hirooka K, Ono A, Nakano Y, Nishiyama A, Tsujikawa A. The relationship between the renin-angiotensin-aldosterone system and NMDA receptormediated signal and the prevention of retinal ganglion cell death. Invest Ophthalmol Vis Sci. 2017;58:139758: -140358: . DOI:10.1167 PURPOSE. Excitotoxicity, which is due to glutamate-induced toxic effects on the retinal ganglion cell (RGC), is one of several mechanisms of RGC loss. The renin-angiotensinaldosterone system (RAAS) has also been implicated in RGC death. Therefore, it is important to determine the exact relationship between the RAAS and N-methyl-d-aspartate (NMDA) receptor-mediated signal in order to prevent RGC death.METHODS. N-methyl-d-aspartate or aldosterone was injected into the vitreous body. After intravitreal injection of NMDA or aldosterone, animals were treated with spironolactone or memantine. Retinal damage was evaluated by measuring the number of RGCs at 4 weeks after local administration of aldosterone or at 2 weeks after local administration of NMDA. Vitreous humor levels of aldosterone were measured using enzyme immunoassay kits. RESULTS.A significantly decreased number of RGCs were observed after intravitreal injection of NMDA. Although spironolactone did not show any neuroprotective effects, memantine significantly reduced NMDA-induced degeneration in the retina. Furthermore, a significant decrease in the number of RGCs was observed after an intravitreal injection of aldosterone. While memantine did not exhibit any neuroprotective effects, spironolactone caused a significant reduction in the aldosterone-induced degeneration in the retina. There was no change in the aldosterone concentration in the vitreous humor after an NMDA injection.CONCLUSION. Our findings indirectly show that there is no relationship between the RAAS and NMDA receptor-mediated signal with regard to RGC death.Keywords: aldosterone, retinal ganglion cell, NMDA, glutamate W ithin the central nervous system, including the retina, glutamate functions as a major excitatory neurotransmitter. [1][2][3] Various diseases of the eye, which include glaucoma 4,5 and retinal ischemia, 6,7 have been shown to be associated with the glutamate receptor-mediated excitotoxicity. Glutamate excitotoxicity triggered by overactivation of the N-methyl-Daspartate (NMDA) receptors may be a potential risk factor for retinal ganglion cell (RGC) death.8 Indeed, it has been reported in an animal model that there is a decrease in the RGCs after an intravitreal injection of NMDA.9 One of the NMDA antagonists that has been demonstrated to have therapeutic potential against several central nervous system disorders is memantine (1-amino-3,5-dimethyladamantane). 10 Previous studies examined the use of memantine in several animal models of glaucoma and reported finding that this antagonist might possibility provide neuroprotection, although it was not successful in recent clinical trials. [11][12][13] Since multiple mechanisms can to lead to RGC death, this suggests that a neuroprotectant w...

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Cardiorenal benefits of mineralocorticoid antagonists in CKD and type 2 diabetes

Haller

2022

Herz

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Activation of the aldosterone/mineralocorticoid receptor system and protective effects of mineralocorticoid receptor antagonism in retinal ischemia-reperfusion injury

Cited by 22 publications

References 26 publications

Reduction of Acute Lung Injury by Administration of Spironolactone After Intestinal Ischemia and Reperfusion in Rats

Reduction of Acute Lung Injury by Administration of Spironolactone After Intestinal Ischemia and Reperfusion in Rats

The Relationship Between the Renin-Angiotensin–Aldosterone System and NMDA Receptor-Mediated Signal and the Prevention of Retinal Ganglion Cell Death

Cardiorenal benefits of mineralocorticoid antagonists in CKD and type 2 diabetes

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