RIPK3 mediates renal tubular epithelial cell apoptosis in endotoxin‑induced acute kidney injury

Zhang, Shu; Li, Ruizhao; Dong, Wei; Yang, Huan; Zhang, Li; Chen, Yuanhan; Wang, Weidong; Li, Chunling; Wu, Yanhua; Ye, Zhiming; Zhao, Xingchen; Li, Zhilian; Zhang, Mengxi; Liu, Shuangxin; Liang, Xinling

doi:10.3892/mmr.2019.10416

Cited by 19 publications

(29 citation statements)

References 51 publications

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“…We observed higher urinary RIPK3 in patients with sepsis. It was further confirmed that RIPK3 inhibition reduced endotoxin-(in vivo) or lipopolysaccharide (in vitro)-induced tubular cell apoptosis [30]. The apoptotic and necroptotic pathways of cell death converge at the mitochondria.…”

Section: Sepsis-induced Akimentioning

confidence: 72%

Mitochondrial dysfunction in kidney injury, inflammation, and disease: Potential therapeutic approaches

Bhatia¹,

Capili²,

Choi

2020

Kidney Res Clin Pract

115

104

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Renal inflammation and tissue damage during acute kidney injury (AKI) and chronic kidney disease (CKD) have been linked to mitochondrial structural and functional alterations [1,2]. Mitochondria are a highly complex interconnected network of organelles that fulfill cellular energy needs. The kidney, an organ with high energy demands, is rich in mitochondria. Mitochondrial dysfunction arising from disturbances in the regulation of the mitochondrial electron transport chain (ETC), proton gradient, and membrane potential results in reduced adenosine triphosphate (ATP) and increased production of mitochondrial-derived reactive oxygen species (mROS), which promotes kidney injury and inflammation [3,4].

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Section: Sepsis-induced Akimentioning

confidence: 72%

Mitochondrial dysfunction in kidney injury, inflammation, and disease: Potential therapeutic approaches

Bhatia¹,

Capili²,

Choi

2020

Kidney Res Clin Pract

115

104

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“…An important effect associated with oxidative damage is that the renal tubular epithelial cells are the first involved in acute renal injury ( 16 , 17 ). Emerging evidence indicates that miR-30a-5p acts as a suppressor for cancer, regulating the growth, migration, and invasion of various tumors, including maintaining renal function during acute renal injury ( 18 – 20 ).…”

Section: Discussionmentioning

confidence: 99%

miR‑30a‑5p inhibits hypoxia/reoxygenation‑induced oxidative stress and apoptosis in HK‑2 renal tubular epithelial cells by targeting glutamate dehydrogenase 1 (GLUD1)

He¹,

Lang²,

Cheng³

et al. 2020

Oncol Rep

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MicroRNAs (miRNAs) are reported to be involved in renal hypoxia/reoxygenation (H/R) damage. To investigate this further, human kidney (HK-2) cells were cultured, subjected to H/R and the function of miR-30a-5p and glutamate dehydrogenase 1 (GLUD1) was evaluated. The results showed that, miR-30-5p was downregulated and GLUD1 was upregulated in HK-2 cells exposed to H/R. The relationship between miR-30a-5p and GLUD1 was determined using dual luciferase assays. Primary HK-2 cells were cultured in H/R and transfected with negative control 1 (NC1), negative control 2 (NC2), mimic, inhibitor or GLUD1 siRNA plasmids. Reactive oxygen species (ROS) generation, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities, and the rate of apoptosis in HK-2 cells were assessed. The results showed that, miR-30a-5p mimic reduced the production of ROS in HK-2 cells treated with H/R, but increased the activity of SOD, CAT and GPx. In addition, miR-30a-5p mimic significantly decreased H/R-mediated apoptosis, decreased the expression of bax and activity of caspase-3 and enhanced the expression of bcl-2. However, miR-30a-5p inhibitor showed the opposite effect with regard to the degree of oxidative damage and apoptosis in H/R-induced HK-2 cells. Silencing GLUD1 rescued the influence of miR-30a-5p inhibitor on oxidative injury and apoptosis in HK-2 cells stimulated with H/R. These results demonstrated that under H/R conditions, miR-30a-5p can reduce oxidative stress in vitro by targeting GLUD1, which may be a novel therapeutic target for liver failure and worth further study.

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“…The pleiotropic cytokine TNF-α has a particular role in the initiation of cell-survival signaling molecules such as upregulation of anti-apoptotic molecules Bcl-2, and survivin (an inhibitor of apoptosis—IAP) through activation of nuclear factor-kappa (NF-κB) [ 5 ]. In addition to the severe inflammatory syndrome, LPS activates Toll-like receptor 4 (TLR4) that is present in the membrane of immune cells and renal tubular epithelial cells, triggering the excessive release of proinflammatory cytokines, oxidative stress, and tubular cell apoptosis [ 3 , 6 ]. Severe tubular cell apoptosis plays an important role in LPS-induced AKI, showing caspase-3-positivity in tubular epithelial cells even at the early phase of AKI [ 3 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Protective Effects of Simvastatin on Endotoxin-Induced Acute Kidney Injury through Activation of Tubular Epithelial Cells’ Survival and Hindering Cytochrome C-Mediated Apoptosis

Nežić

Škrbić

Amidžić

et al. 2020

IJMS

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Increasing evidence suggests that apoptosis of tubular cells and renal inflammation mainly determine the outcome of sepsis-associated acute kidney injury (AKI). The study aim was to investigate the molecular mechanism involved in the renoprotective effects of simvastatin in endotoxin (lipopolysaccharide, LSP)-induced AKI. A sepsis model was established by intraperitoneal injection of a single non-lethal LPS dose after short-term simvastatin pretreatment. The severity of the inflammatory injury was expressed as renal damage scores (RDS). Apoptosis of tubular cells was detected by Terminal deoxynucleotidyl transferase-mediated dUTP Nick End Labeling (TUNEL assay) (apoptotic DNA fragmentation, expressed as an apoptotic index, AI) and immunohistochemical staining for cleaved caspase-3, cytochrome C, and anti-apoptotic Bcl-xL and survivin. We found that endotoxin induced severe renal inflammatory injury (RDS = 3.58 ± 0.50), whereas simvastatin dose-dependently prevented structural changes induced by LPS. Furthermore, simvastatin 40 mg/kg most profoundly attenuated tubular apoptosis, determined as a decrease of cytochrome C, caspase-3 expression, and AIs (p < 0.01 vs. LPS). Conversely, simvastatin induced a significant increase of Bcl-XL and survivin, both in the strong inverse correlations with cleaved caspase-3 and cytochrome C. Our study indicates that simvastatin has cytoprotective effects against LPS-induced tubular apoptosis, seemingly mediated by upregulation of cell-survival molecules, such as Bcl-XL and survivin, and inhibition of the mitochondrial cytochrome C and downstream caspase-3 activation.

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RIPK3 mediates renal tubular epithelial cell apoptosis in endotoxin‑induced acute kidney injury

Cited by 19 publications

References 51 publications

Mitochondrial dysfunction in kidney injury, inflammation, and disease: Potential therapeutic approaches

Mitochondrial dysfunction in kidney injury, inflammation, and disease: Potential therapeutic approaches

miR‑30a‑5p inhibits hypoxia/reoxygenation‑induced oxidative stress and apoptosis in HK‑2 renal tubular epithelial cells by targeting glutamate dehydrogenase 1 (GLUD1)

Protective Effects of Simvastatin on Endotoxin-Induced Acute Kidney Injury through Activation of Tubular Epithelial Cells’ Survival and Hindering Cytochrome C-Mediated Apoptosis

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