Peroxynitrite formation and apoptosis in transgenic sickle cell mouse kidneys

Bank, Norman; Kiroycheva, Militza; Ahmed, Fayyaz; Anthony, Gillian M.; Fabry, Mary E.; Nagel, Ronald L.; Singhal, Pravin C.

doi:10.1046/j.1523-1755.1998.00148.x

Cited by 57 publications

(33 citation statements)

References 49 publications

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“…The instability of NO and ROS make them unlikely mediators of apoptosis in our in vitro system, since the soluble molecules responsible must be stable for at least a number of hours, if not days. However, NO and superoxide (ROS) rapidly combine to form the more stable and potent oxidant, peroxynitrite (38), which is capable of inciting tubular cell apoptosis (39) and generating longer-lived apoptosis-inducing mediators (40,41). Therefore, it is more probable that a relatively stable by-product of ROS mediates TEC apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Reduced Macrophage Recruitment, Proliferation, and Activation in Colony-Stimulating Factor-1-Deficient Mice Results in Decreased Tubular Apoptosis During Renal Inflammation

Lenda

Kikawada

Stanley

et al. 2003

The Journal of Immunology

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Kidney tubular epithelial cell (TEC) death may be dependent on the number and activation state of macrophages (Mφ) during inflammation. Our prior studies indicate that activated Mφ release soluble mediators that incite TEC death, and reducing intrarenal Mφ during kidney disease diminishes TEC apoptosis. CSF-1 is required for Mφ proliferation and survival. We hypothesized that in the absence of CSF-1, Mφ-mediated TEC apoptosis would be prevented during renal inflammation. To test this hypothesis, we evaluated renal inflammation during unilateral ureter obstruction in CSF-1-deficient (Csf1op/Csf1op) mice. We detected fewer Mφ and T cells and less apoptotic TEC in the obstructed kidneys of Csf1op/Csf1op mice compared with wild-type (WT) mice. The decrease in intrarenal Mφ resulted from diminished recruitment and proliferation, not enhanced apoptosis. CSF-1 enhanced Mφ activation. There were far fewer activated (CD69, CD23, Ia, surface expression) Mφ in obstructed CSF-1-deficient compared with WT obstructed kidneys. Similarly, bone marrow Mφ preincubated with anti-CSF-1 receptor Ab or anti-CSF-1 neutralizing Ab were resistant to LPS- and IFN-γ-induced activation. We detected fewer apoptotic-inducing molecules (reactive oxygen species, TNF-α, inducible NO synthase) in 1) Mφ propagated from obstructed Csf1op/Csf1op compared with WT kidneys, and 2) WT bone marrow Mφ blocked with anti-CSF-1 receptor or anti-CSF-1 Ab compared with the isotype control. Furthermore, blocking CSF-1 or the CSF-1 receptor induced less TEC apoptosis than the isotype control. We suggest that during renal inflammation, CSF-1 mediates Mφ recruitment, proliferation, activation, and, in turn, TEC apoptosis.

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Section: Discussionmentioning

confidence: 99%

Reduced Macrophage Recruitment, Proliferation, and Activation in Colony-Stimulating Factor-1-Deficient Mice Results in Decreased Tubular Apoptosis During Renal Inflammation

Lenda

Kikawada

Stanley

et al. 2003

The Journal of Immunology

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“…• -induced nitration of proteins (29,30), are abundantly generated in sickle-cell mouse kidneys (31,32). We evaluated the effects of ETR blockade on nitrative stress during acute VOC by assessing nitration of renal tissues in SAD and WT mice.…”

Section: Endothelin Receptors Contribute To H/r-induced Neutrophil Rementioning

confidence: 99%

Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell disease

Sabaa¹,

Franceschi²,

Bonnin³

et al. 2008

J. Clin. Invest.

122

129

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Patients with sickle-cell disease (SCD) suffer from tissue damage and life-threatening complications caused by vasoocclusive crisis (VOC). Endothelin receptors (ETRs) are mediators of one of the most potent vasoconstrictor pathways in mammals, but the relationship between vasoconstriction and VOC is not well understood. We report here that pharmacological inhibition of ETRs prevented hypoxia-induced acute VOC and organ damage in a mouse model of SCD. An in vivo ultrasonographic study of renal hemodynamics showed a substantial increase in endothelin-mediated vascular resistance during hypoxia/reoxygenation-induced VOC. This increase was reversed by administration of the dual ETR antagonist (ETRA) bosentan, which had pleiotropic beneficial effects in vivo. It prevented renal and pulmonary microvascular congestion, systemic inflammation, dense rbc formation, and infiltration of activated neutrophils into tissues with subsequent nitrative stress. Bosentan also prevented death of sickle-cell mice exposed to a severe hypoxic challenge. These findings in mice suggest that ETRA could be a potential new therapy for SCD, as it may prevent acute VOC and limit organ damage in sickle-cell patients.

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“…11 Nitrotyrosine is formed when peroxynitrite interacts with tyrosine and may interfere with the activity of enzymes and proteins involved in regulatory cascades or ion transport. One mechanism of peroxynitrite formation occurs when NOS is active at low levels of arginine.…”

Section: Introductionmentioning

confidence: 99%

Arginine supplementation of sickle transgenic mice reduces red cell density and Gardos channel activity

Romero

Suzuka

Nagel

et al. 2002

Blood

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Nitric oxide (NO), essential for maintaining vascular tone, is produced from arginine by nitric oxide synthase. Plasma arginine levels are low in sickle cell anemia, and it is reported here that low plasma arginine is also found in our sickle transgenic mouse model that expresses human ␣, human ␤ S , and human ␤ S-Antilles and is homozygous for the mouse ␤ major deletion (S؉S-Antilles). S؉S-Antilles mice were supplemented with a 4-fold increase in arginine that was maintained for several months.

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Peroxynitrite formation and apoptosis in transgenic sickle cell mouse kidneys

Cited by 57 publications

References 49 publications

Reduced Macrophage Recruitment, Proliferation, and Activation in Colony-Stimulating Factor-1-Deficient Mice Results in Decreased Tubular Apoptosis During Renal Inflammation

Reduced Macrophage Recruitment, Proliferation, and Activation in Colony-Stimulating Factor-1-Deficient Mice Results in Decreased Tubular Apoptosis During Renal Inflammation

Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell disease

Arginine supplementation of sickle transgenic mice reduces red cell density and Gardos channel activity

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