Publications (2)7.08 Total impact
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Article: Previous ischemia and reperfusion injury results in resistance of the kidney against subsequent ischemia and reperfusion insult in mice; a role for the Akt signal pathway.
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ABSTRACT: BACKGROUND: Kidneys previously exposed to ischemia and reperfusion (I/R), pre-conditioned by I/R, are less susceptible to subsequent I/R injury. Here, we investigated the role for protein kinase B (Akt) survival signaling pathways including anti-apoptosis pathways in the reduced susceptibility of I/R-pre-conditioned kidneys.METHODS: Mice were exposed to either a single I/R pre-conditioning event (SIRPC, 30 min of bilateral renal ischemia followed by 8 days of reperfusion) or sham-operation (non-SIRPC) and then subjected to either 30 min of bilateral renal ischemia or sham-operation (sham). Some of the mice received intra-peritoneal administrations of wortmannin, which is an inhibitor of phosphatidylinositol-3 kinase, PI3K.RESULTS: Thirty minutes of bilateral renal ischemia in non-SIRPC mice induced a dramatic increase in plasma creatinine (PCr) levels, but this was not observed in the SIRPC mouse. Consistent with the PCr results, tubular damage and apoptotic tubular cell death were more severe in the non-SIRPC mouse kidney than in the SIRPC mice. SIRPC increased the levels of phosphorylated-Akt and -Bad expression as well as the ratio of Bcl-2 to Bax expression in the kidney. I/R resulted in greater increases of phosphorylated-Akt and -Bad, Bcl-xL and Bcl-2, but a lower level of increase of Bax, in the SIRPC mouse kidneys than those in the non-SIRPC-mouse kidneys. Treatment with wortmannin during the SIRPC period inhibited SIRPC-induced increase in phosphorylated-Akt and -Bad expressions and eliminated tolerance of SIRPC mice kidneys to I/R insult.CONCLUSION: Ischemic pre-conditioning confers renal resistance to I/R-induced apoptosis via activation of the Akt signal pathway.Nephrology Dialysis Transplantation 05/2012; · 3.40 Impact Factor -
Article: Role of cytosolic NADP+-dependent isocitrate dehydrogenase in ischemia-reperfusion injury in mouse kidney.
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ABSTRACT: Cytosolic NADP+-dependent isocitrate dehydrogenase (IDPc) synthesizes reduced NADP (NADPH), which is an essential cofactor for the generation of reduced glutathione (GSH), the most abundant and important antioxidant in mammalian cells. We investigated the role of IDPc in kidney ischemia-reperfusion (I/R) in mice. The activity and expression of IDPc were highest in the cortex, modest in the outer medulla, and lowest in the inner medulla. NADPH levels were greatest in the cortex. IDPc expression in the S1 and S2 segments of proximal tubules was higher than in the S3 segment, which is much more susceptible to I/R. IDPc protein was also highly expressed in the mitochondrion-rich intercalated cells of the collecting duct. IDPc activity was 10- to 30-fold higher than the activity of glucose-6-phosphate dehydrogenase, another producer of cytosolic NADPH, in various kidney regions. This study identifies that IDPc may be the primary source of NADPH in the kidney. I/R significantly reduced IDPc expression and activity and NADPH production and increased the ratio of oxidized glutathione to total glutathione [GSSG/(GSH+GSSG)], resulting in kidney dysfunction, tubular cell damage, and lipid peroxidation. In LLC-PK(1) cells, upregulation of IDPc by IDPc gene transfer protected the cells against hydrogen peroxide, enhancing NADPH production, inhibiting the increase of GSSG/(GSH+GSSG), and reducing lipid peroxidation. IDPc downregulation by small interference RNA treatment presented results contrasting with the upregulation. In conclusion, these results demonstrate that IDPc is expressed differentially along tubules in patterns that may contribute to differences in susceptibility to injury, is a major enzyme in cytosolic NADPH generation in kidney, and is downregulated with I/R.American journal of physiology. Renal physiology 01/2009; 296(3):F622-33. · 3.68 Impact Factor
