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Sodium nitrite protects against kidney injury induced by brain death and improves post-transplant function.

Kelpke SS, Chen B, Bradley KM, Teng X, Chumley P, Brandon A, Yancey B, Moore B, Head H, Viera L, Thompson JA, Crossman DK, Bray MS, Eckhoff DE, Agarwal A, Patel RP - Kidney Int. (2012)

Bottom Line: Renal injury induced by brain death is characterized by ischemia and inflammation, and limiting it is a therapeutic goal that could improve outcomes in kidney transplantation.Brain death resulted in decreased circulating nitrite levels and increased infiltrating inflammatory cell infiltration into the kidney.Allografts collected from nitrite-treated brain-dead rats showed significant improvement in function over the first 2 to 4 days after transplantation compared with untreated brain-dead animals.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

ABSTRACT
Renal injury induced by brain death is characterized by ischemia and inflammation, and limiting it is a therapeutic goal that could improve outcomes in kidney transplantation. Brain death resulted in decreased circulating nitrite levels and increased infiltrating inflammatory cell infiltration into the kidney. Since nitrite stimulates nitric oxide signaling in ischemic tissues, we tested whether nitrite therapy was beneficial in a rat model of brain death followed by kidney transplantation. Nitrite, administered over 2 h of brain death, blunted the increased inflammation without affecting brain death-induced alterations in hemodynamics. Kidneys were transplanted after 2 h of brain death and renal function followed over 7 days. Allografts collected from nitrite-treated brain-dead rats showed significant improvement in function over the first 2 to 4 days after transplantation compared with untreated brain-dead animals. Gene microarray analysis after 2 h of brain death without or with nitrite therapy showed that the latter significantly altered the expression of about 400 genes. Ingenuity Pathway Analysis indicated that multiple signaling pathways were affected by nitrite, including those related to hypoxia, transcription, and genes related to humoral immune responses. Thus, nitrite therapy attenuates brain death-induced renal injury by regulating responses to ischemia and inflammation, ultimately leading to better post-transplant kidney function.

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Nitrite treatment prevents BD induced increases in markers of leukocyte infiltration but not oxidative stressPanel A: Representative immunofluoresence images for Cd11a, Cd11b, Cd18 and 3-HNE (red staining) in control, BD (2h) or BD (2h) + nitrite. Blue staining represents nuclei stained with Hoechst 33342. Panel B: Western blot analysis for expression of CD11b / β-actin ratios. Data show mean ± SEM (n=2–6) and are normalized to BD alone group (set at 100%). P<0.001 by 1-way ANOVA with *P < 0.05 relative to sham, **P<0.05 relative to BD alone, #P<0.01 relative to BD alone by Tukey’s Multiple comparison post test.
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Figure 4: Nitrite treatment prevents BD induced increases in markers of leukocyte infiltration but not oxidative stressPanel A: Representative immunofluoresence images for Cd11a, Cd11b, Cd18 and 3-HNE (red staining) in control, BD (2h) or BD (2h) + nitrite. Blue staining represents nuclei stained with Hoechst 33342. Panel B: Western blot analysis for expression of CD11b / β-actin ratios. Data show mean ± SEM (n=2–6) and are normalized to BD alone group (set at 100%). P<0.001 by 1-way ANOVA with *P < 0.05 relative to sham, **P<0.05 relative to BD alone, #P<0.01 relative to BD alone by Tukey’s Multiple comparison post test.

Mentions: To evaluate the mechanisms underlying improved renal function post transplantation of kidneys collected from nitrite treated BD rats, expression of several markers / mediators of inflammation and oxidative stress were measured in kidneys collected after 2h of brain death. Figure 4 shows representative immunofluoresence staining for the adhesion molecules CD11a, CD11b, CD18 and the protein adduct of 3-HNE. All these markers increased after 2h BD and showed a tubular location consistent with increased inflammation and oxidative stress. Nitrite treatment decreased staining for CD11a and CD11b, further confirmed by significant decrease in CD11b measured by western blotting (Figure 4B). Interestingly, nitrite did not affect 3-HNE staining. No changes in expression of the pro-inflammatory peroxidase myeloperoxidase, the inflammatory marker 3-nitrotyrosine, or adhesion molecules ICAM-1, VCAM-1 were observed in BD exposed rats (not shown).


Sodium nitrite protects against kidney injury induced by brain death and improves post-transplant function.

Kelpke SS, Chen B, Bradley KM, Teng X, Chumley P, Brandon A, Yancey B, Moore B, Head H, Viera L, Thompson JA, Crossman DK, Bray MS, Eckhoff DE, Agarwal A, Patel RP - Kidney Int. (2012)

Nitrite treatment prevents BD induced increases in markers of leukocyte infiltration but not oxidative stressPanel A: Representative immunofluoresence images for Cd11a, Cd11b, Cd18 and 3-HNE (red staining) in control, BD (2h) or BD (2h) + nitrite. Blue staining represents nuclei stained with Hoechst 33342. Panel B: Western blot analysis for expression of CD11b / β-actin ratios. Data show mean ± SEM (n=2–6) and are normalized to BD alone group (set at 100%). P<0.001 by 1-way ANOVA with *P < 0.05 relative to sham, **P<0.05 relative to BD alone, #P<0.01 relative to BD alone by Tukey’s Multiple comparison post test.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3412933&req=5

Figure 4: Nitrite treatment prevents BD induced increases in markers of leukocyte infiltration but not oxidative stressPanel A: Representative immunofluoresence images for Cd11a, Cd11b, Cd18 and 3-HNE (red staining) in control, BD (2h) or BD (2h) + nitrite. Blue staining represents nuclei stained with Hoechst 33342. Panel B: Western blot analysis for expression of CD11b / β-actin ratios. Data show mean ± SEM (n=2–6) and are normalized to BD alone group (set at 100%). P<0.001 by 1-way ANOVA with *P < 0.05 relative to sham, **P<0.05 relative to BD alone, #P<0.01 relative to BD alone by Tukey’s Multiple comparison post test.
Mentions: To evaluate the mechanisms underlying improved renal function post transplantation of kidneys collected from nitrite treated BD rats, expression of several markers / mediators of inflammation and oxidative stress were measured in kidneys collected after 2h of brain death. Figure 4 shows representative immunofluoresence staining for the adhesion molecules CD11a, CD11b, CD18 and the protein adduct of 3-HNE. All these markers increased after 2h BD and showed a tubular location consistent with increased inflammation and oxidative stress. Nitrite treatment decreased staining for CD11a and CD11b, further confirmed by significant decrease in CD11b measured by western blotting (Figure 4B). Interestingly, nitrite did not affect 3-HNE staining. No changes in expression of the pro-inflammatory peroxidase myeloperoxidase, the inflammatory marker 3-nitrotyrosine, or adhesion molecules ICAM-1, VCAM-1 were observed in BD exposed rats (not shown).

Bottom Line: Renal injury induced by brain death is characterized by ischemia and inflammation, and limiting it is a therapeutic goal that could improve outcomes in kidney transplantation.Brain death resulted in decreased circulating nitrite levels and increased infiltrating inflammatory cell infiltration into the kidney.Allografts collected from nitrite-treated brain-dead rats showed significant improvement in function over the first 2 to 4 days after transplantation compared with untreated brain-dead animals.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

ABSTRACT
Renal injury induced by brain death is characterized by ischemia and inflammation, and limiting it is a therapeutic goal that could improve outcomes in kidney transplantation. Brain death resulted in decreased circulating nitrite levels and increased infiltrating inflammatory cell infiltration into the kidney. Since nitrite stimulates nitric oxide signaling in ischemic tissues, we tested whether nitrite therapy was beneficial in a rat model of brain death followed by kidney transplantation. Nitrite, administered over 2 h of brain death, blunted the increased inflammation without affecting brain death-induced alterations in hemodynamics. Kidneys were transplanted after 2 h of brain death and renal function followed over 7 days. Allografts collected from nitrite-treated brain-dead rats showed significant improvement in function over the first 2 to 4 days after transplantation compared with untreated brain-dead animals. Gene microarray analysis after 2 h of brain death without or with nitrite therapy showed that the latter significantly altered the expression of about 400 genes. Ingenuity Pathway Analysis indicated that multiple signaling pathways were affected by nitrite, including those related to hypoxia, transcription, and genes related to humoral immune responses. Thus, nitrite therapy attenuates brain death-induced renal injury by regulating responses to ischemia and inflammation, ultimately leading to better post-transplant kidney function.

Show MeSH
Related in: MedlinePlus