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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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Related in: MedlinePlus

Effects of nitrite on BD (2h) induced changes in gene expression in the kidneyReal time-PCR analyses of indicated genes was performed. Data show fold change relative to BD alone and are mean ± SEM, n=3. For all up-regulated genes, P <0.05 by t-test.
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Figure 5: Effects of nitrite on BD (2h) induced changes in gene expression in the kidneyReal time-PCR analyses of indicated genes was performed. Data show fold change relative to BD alone and are mean ± SEM, n=3. For all up-regulated genes, P <0.05 by t-test.

Mentions: Supplementary Figure 1A shows a heat map showing that nitrite therapy altered the expression of 381 genes relative to BD alone, with 264 being down- and 117 up-regulated. Ingenuity Pathway Analysis (IPA) generated 19 networks (with >1 focus molecule identified) affected by nitrite therapy (Table 1) and consistent with recent reports showing nitrite therapy has diverse effects of gene expression profiles 33. Interestingly, the highest ranked network was related to the humoral immune response, an established key element of inflammatory tissue injury during BD in the kidney 34. Supplementary Figure 2 illustrates the top 5 canonical signaling pathways that are most significantly affected by nitrite therapy (and are elF2, Notch, HIF1α, Nrf2 / oxidative stress and elF4 / p70S6K respectively) and also indicate specific genes that maybe modulated by nitrite therapy. Supplementary Figure 1B lists the number of genes that are down- or up-regulated within these pathways. Figure 5 shows real time-PCR analyses of 9 selected genes encompassing the top 5 pathways and separates these into those that either did not change or were up-regulated by nitrite + BD relative to BD alone. Supplementary Table 1 compares mRNA array data with real time-PCR data and shows that nitrite dependent changes indicated by mRNA arrays were validated with 4 of the selected genes. Finally, since one of the genes validated to increase with nitrite therapy was Keap1, relative expression of Nrf2 was also determined. Figure 5 shows that this too was increased with nitrite therapy relative to BD alone.


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)

Effects of nitrite on BD (2h) induced changes in gene expression in the kidneyReal time-PCR analyses of indicated genes was performed. Data show fold change relative to BD alone and are mean ± SEM, n=3. For all up-regulated genes, P <0.05 by t-test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3412933&req=5

Figure 5: Effects of nitrite on BD (2h) induced changes in gene expression in the kidneyReal time-PCR analyses of indicated genes was performed. Data show fold change relative to BD alone and are mean ± SEM, n=3. For all up-regulated genes, P <0.05 by t-test.
Mentions: Supplementary Figure 1A shows a heat map showing that nitrite therapy altered the expression of 381 genes relative to BD alone, with 264 being down- and 117 up-regulated. Ingenuity Pathway Analysis (IPA) generated 19 networks (with >1 focus molecule identified) affected by nitrite therapy (Table 1) and consistent with recent reports showing nitrite therapy has diverse effects of gene expression profiles 33. Interestingly, the highest ranked network was related to the humoral immune response, an established key element of inflammatory tissue injury during BD in the kidney 34. Supplementary Figure 2 illustrates the top 5 canonical signaling pathways that are most significantly affected by nitrite therapy (and are elF2, Notch, HIF1α, Nrf2 / oxidative stress and elF4 / p70S6K respectively) and also indicate specific genes that maybe modulated by nitrite therapy. Supplementary Figure 1B lists the number of genes that are down- or up-regulated within these pathways. Figure 5 shows real time-PCR analyses of 9 selected genes encompassing the top 5 pathways and separates these into those that either did not change or were up-regulated by nitrite + BD relative to BD alone. Supplementary Table 1 compares mRNA array data with real time-PCR data and shows that nitrite dependent changes indicated by mRNA arrays were validated with 4 of the selected genes. Finally, since one of the genes validated to increase with nitrite therapy was Keap1, relative expression of Nrf2 was also determined. Figure 5 shows that this too was increased with nitrite therapy relative to BD alone.

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