Renal nitric oxide synthases in transgenic sickle cell mice

Bank, Norman; Aynedjian, Hagop S.; Qiu, Ju; Osei, Suzette Y.; Ahima, Rexford S.; Fabry, Mary E.; Nagel, Ronald L.

doi:10.1038/ki.1996.301

Cited by 88 publications

(67 citation statements)

References 38 publications

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“…The occurrence of xanthine oxidasederived, O 2 . -dependent inhibition of ⅐ NO-mediated vascular relaxation in SCD vessels (53) and the elevated expression of NOS2 (54,55) in the kidney and liver of SCD mice and human ( Figs. 1 and 2) also reinforces the concept that elevated rates of production of the oxidizing and nitrating species ONOO Ϫ occurs in SCD.…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide-dependent Generation of Reactive Species in Sickle Cell Disease

Aslan¹,

Ryan²,

Townes³

et al. 2003

Journal of Biological Chemistry

158

105

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The intermittent vascular occlusion occurring in sickle cell disease (SCD) leads to ischemia-reperfusion injury and activation of inflammatory processes including enhanced production of reactive oxygen species and increased expression of inducible nitric-oxide synthase (NOS2). Appreciating that impaired nitric oxide-dependent vascular function and the concomitant formation of oxidizing and nitrating species occur in concert with increased rates of tissue reactive oxygen species production, liver and kidney NOS2 expression, tissue 3-nitrotyrosine (NO 2 Tyr) formation and apoptosis were evaluated in human SCD tissues and a murine model of SCD. Liver and kidney NOS2 expression and NO 2 Tyr immunoreactivity were significantly increased in SCD mice and humans, but not in nondiseased tissues. TdTmediated nick end-label (TUNEL) staining showed apoptotic cells in regions expressing elevated levels of NOS2 and NO 2 Tyr in all SCD tissues. Gas chromatography mass spectrometry analysis revealed increased plasma protein NO 2 Tyr content and increased levels of hepatic and renal protein NO 2 Tyr derivatives in SCD (21.4 ؎ 2.6 and 37.5 ؎ 7.8 ng/mg) versus wild type mice (8.2 ؎ 2.2 and 10 ؎ 1.2 ng/mg), respectively. Western blot analysis and immunoprecipitation of SCD mouse liver and kidney proteins revealed one principal NO 2 Tyr-containing protein of 42 kDa, compared with controls. Enzymatic in-gel digestion and MALDI-TOF mass spectrometry identified this nitrated protein as actin. Electrospray ionization and fragment analysis by tandem mass spectrometry revealed that 3 of 15 actin tyrosine residues are nitrated (Tyr 91 , Tyr 198 , and Tyr 240 ) at positions that significantly modify actin assembly. Confocal microscopy of SCD human and mouse tissues revealed that nitration led to morphologically distinct disorganization of filamentous actin. In aggregate, we have observed that the hemoglobin point mutation of sickle cell disease that mediates hemoglobin polymerization defects is translated, via inflammatory oxidant reactions, into defective cytoskeletal polymerization.

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Section: Discussionmentioning

confidence: 99%

Nitric Oxide-dependent Generation of Reactive Species in Sickle Cell Disease

Aslan¹,

Ryan²,

Townes³

et al. 2003

Journal of Biological Chemistry

158

105

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“…It was shown that iNOS inhibition significantly limits tissue ischemiareperfusion injury in the liver and kidneys [10][11]; however, inhibition of iNOS attenuated ischemiareperfusion injury in the rat heart [12], but not in the rat lung [13]. Increased iNOS expression was reported in the kidneys of transgenic mice [9], but Nath et al [14] reported the lack of iNOS upregulation in intrarenal vasculature and increased iNOS expression in the glomeruli and distal tubules of sickle mice. Previous attempts to demonstrate increased iNOS expression in SCD-affected tissues have yielded inconclusive results [52][53][54][55].…”

Section: Discussionmentioning

confidence: 99%

“…SCD is also strongly associated with oxidative stress, increased expression of endothelial cell adhesion molecules, and blood adhesion. Increased iNOS expression and NO production have been observed in the kidneys and the liver in SCD patients [8], in mice [2,3,8,9], and in pigs [4]. During the clinically asymptomatic state, NO bioavailability is reduced in SCD patients due to scavenging of NO by cell-free hemoglobin released from hemolyzed sickle erythrocytes [50] and increased arginase activity [51].…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, it was shown that iNOS inhibition significantly limits tissue ischemia-reperfusion injury in the liver and kidneys [10,11]; however, inhibition of iNOS attenuated ischemia-reperfusion injury in the rat heart [12] and did not affect ischemia-reperfusion injury in the rat lung [13]. Increased levels of iNOS expression were shown in the kidneys of transgenic mice [9], but Nath et al [14] reported the lack of upregulation of iNOS in the intrarenal vasculature and increased expression of iNOS in the [15][16][17] and in vitro [18]. It was reported that NOS activity plays a role in stimulating production of NO x .…”

Section: Introductionmentioning

confidence: 96%

“…Increased iNOS expression and a consequent increase in tissue nitrite and nitrate production have been observed in the kidneys and liver of SCD patients [8], mice [2,3,8,9], and pigs [4]. Additionally, it was shown that iNOS inhibition significantly limits tissue ischemia-reperfusion injury in the liver and kidneys [10,11]; however, inhibition of iNOS attenuated ischemia-reperfusion injury in the rat heart [12] and did not affect ischemia-reperfusion injury in the rat lung [13].…”

Section: Introductionmentioning

confidence: 99%

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Nitric oxide in gingival crevicular fluid and nitric oxide synthase expression in the gingiva of patients with sickle cell disease

Güzeldemir

Toygar²,

Bal³

et al. 2011

Turk J Hematol

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Objective: This study aimed to biochemically measure the production of nitric oxide in gingival crevicular fluid and immunohistochemically measure the expression of inducible nitric oxide synthase in the gingiva of patients with sickle cell disease. Additionally, we aimed to obtain insight into the immunopathology of sickle cell disease by comparing inducible nitric oxide synthase levels in patients with sickle cell disease and controls using gingiva and gingival crevicular fluid. Materials and Methods: The study included 20 sickle cell disease patients and 20 healthy controls. Immunohistochemical analysis was used to measure inducible nitric oxide synthase expression in gingiva and nitric oxide levels in gingival crevicular fluid were spectrophotometrically measured. Results: Nitric oxide levels in the patients and controls did not differ significantly (21.2±4.5 and 23.1±2.3 μM L -1 , respectively, p>0.05). There weren't any statistically significant differences in infiltrated inflammatory cells, density of inflammatory cells that stained with inducible nitric oxide synthase, or nitric oxide expression in gingiva between the patient and control groups (p>0.05). Conclusion: To the best of our knowledge this is the first study to examine the expression of inducible nitric oxide synthase in the gingiva and gingival crevicular fluid in patients with sickle cell disease. Using the gingiva and gingival crevicular fluid we were unable to observe sickle cell disease-associated inducible nitric oxide synthase expression and a difference in nitric oxide levels.

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Dysregulated Arginine Metabolism, Hemolysis-Associated Pulmonary Hypertension, and Mortality in Sickle Cell Disease

Morris¹

2005

JAMA

664

682

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L-ARGININE, THE SUBSTRATE FOR nitric oxide (NO) synthesis, is deficient in sickle cell disease (SCD). [1][2][3][4] Increased NO consumption by cell free plasma hemoglobin 5 and reactive oxygen species 6,7 leads to decreased NO bioavailability 8,9 that is exacerbated by decreased availability of the NO synthase substrate L-arginine. This state of resistance to NO is accompanied by a compensatory up-regulation of NO synthase and non-NO-dependent vasodilators. [10][11][12][13] Under conditions of low arginine concentration, NO synthase is uncoupled, producing reactive oxygen species in lieu of NO, 14,15 potentially further reducing NO bioavailability in SCD and enhancing oxidative stress. Recent reports of elevated arginase activity in SCD [16][17][18] offer another avenue for decreasedargininebioavailability.Arginase, an enzyme that converts L-arginine to ornithine and urea, can limit NO bioavailability through increased consumption of the substrate for NO synthase. [19][20][21] Arginase, which is found predominantly

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Renal nitric oxide synthases in transgenic sickle cell mice

Cited by 88 publications

References 38 publications

Nitric Oxide-dependent Generation of Reactive Species in Sickle Cell Disease

Nitric Oxide-dependent Generation of Reactive Species in Sickle Cell Disease

Nitric oxide in gingival crevicular fluid and nitric oxide synthase expression in the gingiva of patients with sickle cell disease

Dysregulated Arginine Metabolism, Hemolysis-Associated Pulmonary Hypertension, and Mortality in Sickle Cell Disease

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