Role of cytosolic NADP + -dependent isocitrate dehydrogenase in ischemia-reperfusion injury in mouse kidney

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Kim J, Jang HS, Park KM. Reactive oxygen species generated by renal ischemia and reperfusion trigger protection against subsequent renal ischemia and reperfusion injury in mice. Am J Physiol Renal Physiol 298: F158 -F166, 2010. First published October 28, 2009 doi:10.1152/ajprenal.00474.2009.-Ischemic preconditioning by a single event of ischemia and reperfusion (SIRPC) dramatically protects renal function against ischemia and reperfusion (I/R) induced several weeks later. We recently reported that reactive oxygen species (ROS) and oxidative stress were sustained in a kidney that had functionally recovered from I/R injury, thus suggesting an association between SIRPC and ROS and oxidative stress. However, the role of ROS in SIRPC remains to be clearly elucidated. To assess the involvement of ROS in SIRPC, mice were subjected to SIRPC (30 min of bilateral renal ischemia and 8 days of reperfusion) and then exposed to I/R injury. Thirty minutes of bilateral renal ischemia in the non-SIRPC mice resulted in a marked increase in plasma creatinine levels 4 and 24 h after reperfusion, which was not observed in the I/R in the SIRPC mice. SIRPC resulted in increases in the levels of kidney superoxide. Administrations of manganese(III) tetrakis(1-methyl-4-pyridyl) porphyrin [MnTMPyP; a cell-permeable superoxide dismutase (SOD) mimetic] and N-acetylcysteine (NAc; a ROS scavenger) to SIRPC mice blocked the SIRPC-induced increase in superoxide levels and removed ϳ48 -64% of the functional protection of the SIRPC kidney. Additionally, these administrations significantly inhibited I/R-induced increases in superoxide formation, hydrogen peroxide production, and lipid peroxidation, along with the inhibition of I/R-induced reductions in the expression and activity of manganese SOD, copper-zinc SOD, and catalase. Furthermore, administrations of MnTMPyP or NAc inhibited the SIRPC-induced increase in inducible nitric oxide synthase expression but did not inhibit the SIRPC-induced increases in heat shock protein-25 expression. In conclusion, the renoprotection afforded by SIRPC was triggered by ROS generated by SIRPC.acute kidney injury; renoprotection; inducible nitric oxygen synthase; heat shock protein ISCHEMIA AND REPERFUSION (I/R) causes acute kidney injury (AKI), which is characterized by high mortality and morbidity, and no effective therapeutic strategy has yet been developed for this condition (3). In addition to direct hypoxic damages induced by reductions in blood flow, I/R injury is associated with a number of factors, including reactive oxygen species (ROS), cytokines, and chemokines, all of which are abundantly generated during I/R (3, 39).ROS are generated under physiological and pathological conditions (9, 38). In physiological conditions, cells produce small amounts of ROS, which could be managed by the scavenging capacity of cells; whereas in pathological conditions they produces excessive ROS, beyond their capacity to scavenge it (9, 29, 38). This excessive ROS generation induces lipid peroxidation, inactivation o...

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Reactive oxygen species generated by renal ischemia and reperfusion trigger protection against subsequent renal ischemia and reperfusion injury in mice

Kim

Jang

Park

2010

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“…Immunofluorescent staining was performed as we previously described (18,21,23). Briefly, to reveal antigen epitope, the sections were boiled in 10 mM sodium citrate buffer (pH 6.0).…”

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confidence: 99%

Loss of poly(ADP-ribose) polymerase 1 attenuates renal fibrosis and inflammation during unilateral ureteral obstruction

Kim¹,

Padanilam

2011

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Poly(ADP-ribose) polymerase 1 (PARP1) contributes to necrotic cell death and inflammation in several disease models; however, the role of PARP1 in fibrogenesis remains to be defined. Here, we tested whether PARP1 was involved in the pathogenesis of renal fibrosis using the unilateral ureteral obstruction (UUO) mouse model. UUO was performed by ligation of the left ureter near the renal pelvis in Parp1-knockout (KO) and wild-type (WT) male mice. After 10 days of UUO, renal PARP1 expression and activation were strongly increased by 6- and 13-fold, respectively. Interstitial fibrosis induced by UUO was significantly attenuated in Parp1-KO kidneys compared with that in WT kidneys at 10 days, but not at 3 days, based on collagen deposition, α-smooth muscle actin (α-SMA), and fibronectin expression. Intriguingly, the UUO kidneys in Parp1-KO mice showed a dramatic decrease in infiltration of neutrophil and reduction in expression of proinflammatory proteins including intercellular adhesion molecule-1, tumor necrosis factor-α, inducible nitric oxide synthase, and toll-like receptor 4 as well as phosphorylation of nuclear factor-κB p65, but not transforming growth factor-β1 (TGF-β1) at both 3 and 10 days. Pharmacological inhibition of PARP1 in rat renal interstitial fibroblast (NRK-49F) cell line or genetic ablation in primary mouse embryonic fibroblast cells did not affect TGF-β1-induced de novo α-SMA expression. Parp1 deficiency significantly attenuated UUO-induced histological damage in the kidney tubular cells, but not apoptosis. These data suggest that PARP1 induces necrotic cell death and contributes to inflammatory signaling pathways that trigger fibrogenesis in obstructive nephropathy.

“…Ischemia causes ATP depletion, which induces necrotic and apoptotic cell death. Following reperfusion, cell damage is worsened to an extent greater than ischemia itself, due to the production of excessive ROS including superoxide anions, hydroxyl radicals, hypochlorous acid, hydrogen peroxide, and peroxynitrite (15,34,42). The ROS levels are excessively increased beyond the antioxidant capacity of the cells.…”

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confidence: 99%

Increased superoxide formation induced by irradiation preconditioning triggers kidney resistance to ischemia-reperfusion injury in mice

Kim

Park²,

Park³

2009

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