Mitochondrial NADP+-Dependent Isocitrate Dehydrogenase Deficiency Exacerbates Mitochondrial and Cell Damage after Kidney Ischemia-Reperfusion Injury

Han, Sang Jun; Jang, Hee‐Seong; Noh, Mi Ra; Kim, Jinu; Kong, Min Jung; Kim, Jee In; Park, Jeen‐Woo; Park, Kwon Moo

doi:10.1681/asn.2016030349

Cited by 57 publications

(45 citation statements)

References 43 publications

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“…We also found that both IPC and Idh2 delivery increase states 1-3 respiratory capacity. This result stands in contrast to that of the report by Han et al, 59 in which IPC decreased IDH2 protein levels; however, our immune blots were performed on protein lysates made from kidney cortex, whereas Han et al 59 used whole-kidney lysates. Their work concluded that downregulation of IDH2 expression resulted in increased injury after AKI.…”

Section: Discussioncontrasting

confidence: 81%

“…Their work concluded that downregulation of IDH2 expression resulted in increased injury after AKI. 59 Taken together, Idh2 delivery mimics IPC, particularly in the ability to confer protection against subsequent ischemic injury. Because it has been difficult to reproduce the protective effect of IPC in the clinical setting, it is possible that timely gene delivery offers an alternative method to prevent ischemic injury.…”

Section: Discussionmentioning

confidence: 99%

“…We believe that IDH2 gene delivery will mimic IPC, because it has been previously reported that its loss is implicated with promoting ischemic disease. 59…”

Section: Discussionmentioning

confidence: 99%

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Exogenous Gene Transmission of Isocitrate Dehydrogenase 2 Mimics Ischemic Preconditioning Protection

Kolb

Corridon²,

Zhang

et al. 2018

JASN

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Ischemic preconditioning confers organ-wide protection against subsequent ischemic stress. A substantial body of evidence underscores the importance of mitochondria adaptation as a critical component of cell protection from ischemia. To identify changes in mitochondria protein expression in response to ischemic preconditioning, we isolated mitochondria from ischemic preconditioned kidneys and sham-treated kidneys as a basis for comparison. The proteomic screen identified highly upregulated proteins, including NADP +-dependent isocitrate dehydrogenase 2 (IDH2), and we confirmed the ability of this protein to confer cellular protection from injury in murine S3 proximal tubule cells subjected to hypoxia. To further evaluate the role of IDH2 in cell protection, we performed detailed analysis of the effects of Idh2 gene delivery on kidney susceptibility to ischemia-reperfusion injury. Gene delivery of IDH2 before injury attenuated the injury-induced rise in serum creatinine (P,0.05) observed in controls and increased the mitochondria membrane potential (P,0.05), maximal respiratory capacity (P,0.05), and intracellular ATP levels (P,0.05) above those in controls. This communication shows that gene delivery of Idh2 can confer organ-wide protection against subsequent ischemiareperfusion injury and mimics ischemic preconditioning.

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Section: Discussioncontrasting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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Exogenous Gene Transmission of Isocitrate Dehydrogenase 2 Mimics Ischemic Preconditioning Protection

Kolb

Corridon²,

Zhang

et al. 2018

JASN

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“…Mounting evidence demonstrated that ROS generation and mitochondrial membrane depolarization may lead to DNA damage and apoptosis [30, 31]. Recent studies indicated that an excess generation of mitochondrial ROS played an important role in the pathogenesis of AKI [32, 33]. The damaged mitochondria are first marked by a change of mitochondrial membrane potential.…”

Section: Discussionmentioning

confidence: 99%

Mitophagy Plays a Protective Role in Iodinated Contrast-Induced Acute Renal Tubular Epithelial Cells Injury

Lei

Zhao

Tang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Contrast induced-acute kidney injury (CI-AKI) is one of the most common causes of acute kidney injury (AKI) in hospitalized patients. Mitophagy, the selective elimination of mitochondria via autophagy, is an important mechanism of mitochondrial quality control in physiological and pathological conditions. In this study, we aimed to determine effects of iohexol and iodixanol on mitochondrial reactive oxygen species (ROS), mitophagy and the potential role of mitophagy in CI-AKI cell models. Methods: Cell viability was measured by cell counting kit-8. Cell apoptosis, mitochondrial ROS and mitochondrial membrane potential were detected by western blot, MitoSOX fluorescence and TMRE staining respectively. Mitophagy was detected by the colocalization of LC3-FITC with MitoTracker Red, western blot and electronic microscope. Results: The results showed that mitophagy was induced in human renal tubular cells (HK-2 cells) under different concentrations of iodinated contrast media. Mitochondrial ROS displayed increased expression after the treatment. Rapamycin (Rap) enhanced mitophagy and alleviated contrast media induced HK-2 cells injury. In contrast, autophagy inhibitor 3-methyladenine (3-MA) down-regulated mitophagy and aggravated cells injury. Conclusions: Together, our finding indicates that iohexol and iodixanol contribute to the generation of mitochondrial ROS and mitophagy. The enhancement of mitophagy can effectively protect the kidney from iodinated contrast (iohexol)-induced renal tubular epithelial cells injury.

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“…Excess generation of mitochondrial ROS has been found in AKI and has been considered to play an important role in the pathogenesis of AKI (20,21). Mitochondrial damage is recognized as a leading cause to many acute renal diseases (22).…”

Section: Discussionmentioning

confidence: 99%

APELA/ELA32 Reduces Iodixanol-induced Apoptosis, Inflammatory Response and Mitochondrial and DNA Damage in Renal Tubular Epithelial Cells

Huang

et al. 2020

Anticancer Res

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Background/Aim: Contrast-induced AKI (CI-AKI) is an important clinical complication of intravascular use of iodinated contrast agents. The aim of the present study was to investigate the renoprotective effect of Apela on contrastinduced acute kidney injury. Materials and Methods: Blood samples from patients exposed to iodinated contrast agent were collected to assay for Apela and creatinine levels. The effects of ELA32 (Apela 32) on iodixanol-induced apoptosis, inflammation response, mitochondrial ROS production and DNA damage were examined in NRK-52E renal tubular epithelial cells. Results: Plasma Apela levels were decreased in patients exposed to the contrast agent. Iodixanol-induced apoptosis was reduced in ELA32 treated NRK-52E cells (p<0.05). ELA32 treatment inhibited iodixanol-induced mitochondrial ROS generation (p<0.01). Iodixanol-induced inflammatory cytokines TNFa and IL-6 and inflammatory genes Nrf2 and ICAM-1 were reduced by ELA32 treatment (p<0.01). Reduced Apela expression in iodixanol-treated cells was partially restored by ELA32 treatment (p<0.05). ELA32 treatment suppressed iodixanol-induced up-regulation of DNA damage-associated gene P-ATR and p-CHK1 as well as apoptosis-associated gene C-caspase 3 (p<0.05). Conclusion: Administration of iodinated contrast agent reduces Apela expression. ELA32 treatment reduces iodixanol-induced apoptosis, inflammatory response and mitochondrial and DNA damage in renal tubular epithelial cells.

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Mitochondrial NADP+-Dependent Isocitrate Dehydrogenase Deficiency Exacerbates Mitochondrial and Cell Damage after Kidney Ischemia-Reperfusion Injury

Cited by 57 publications

References 43 publications

Exogenous Gene Transmission of Isocitrate Dehydrogenase 2 Mimics Ischemic Preconditioning Protection

Exogenous Gene Transmission of Isocitrate Dehydrogenase 2 Mimics Ischemic Preconditioning Protection

Mitophagy Plays a Protective Role in Iodinated Contrast-Induced Acute Renal Tubular Epithelial Cells Injury

APELA/ELA32 Reduces Iodixanol-induced Apoptosis, Inflammatory Response and Mitochondrial and DNA Damage in Renal Tubular Epithelial Cells

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