Caspase-11 promotes cisplatin-induced renal tubular apoptosis through a caspase-3-dependent pathway

Renal tubular injury is the hallmark of cisplatin-induced nephrotoxicity. Caspase-11, a member of the caspase family, plays an important role in inflammation and cell death. However, its role in cisplatin-induced renal tubular injury remains unclear. In cisplatin-treated mice, caspase-11 expression was significantly elevated and the expression of caspase-11 was mainly located in renal tubule. Inhibition of caspase-11 by small-interference RNA or its inhibitor wedelolactone attenuated cisplatin-induced renal dysfunction and tubular injury. In cultured primary renal tubular epithelial cells, cisplatin significantly promoted the expression and activation of caspase-11. Inhibition of caspase-11 by small-interference RNA reduced cisplatin-induced cell apoptosis. Overexpression of caspase-11 promoted cell apoptosis by activating the caspase-3-related cell apoptosis. Furthermore, coimmunoprecipitation results showed there was a direct interaction between caspase-11 and caspase-3, and the interaction was enhanced by cisplatin. The fluorescence confocal microscopy results showed that caspase-11 and caspase-3 were colocalized in the cytoplasm of renal tubular epithelial cells. These results demonstrate that caspase-11 plays an important role in cisplatin-induced renal tubular injury. Caspase-11 promotes renal epithelial cell apoptosis by activating the caspase-3-dependent apoptotic pathway. Caspase-11 might be a potential target for therapeutic treatment against cisplatin-induced nephrotoxicity.

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Mcl-1 is downregulated in cisplatin-induced apoptosis, and proteasome inhibitors restore Mcl-1 and promote survival in renal tubular epithelial cells

AJP Renal Physiology ◽

10.1152/ajprenal.00505.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. F1710-F1717 ◽

Cited By ~ 28

Author(s):

Cheng Yang ◽

Varsha Kaushal ◽

Sudhir V. Shah ◽

Gur P. Kaushal

Keyword(s):

Epithelial Cells ◽

Cytochrome C ◽

Caspase 3 ◽

Proteasome Inhibitors ◽

Mrna Levels ◽

Dependent Manner ◽

Tubular Epithelial Cells ◽

Renal Tubular Epithelial Cells ◽

Renal Tubular ◽

Induced Apoptosis

Mcl-1 is an antiapoptotic member of the Bcl-2 family that plays an important role in cell survival. We demonstrate that proteasome-dependent regulation of Mcl-1 plays a critical role in renal tubular epithelial cell injury from cisplatin. Protein levels of Mcl-1 rapidly declined in a time-dependent manner following cisplatin treatment of LLC-PK1cells. However, mRNA levels of Mcl-1 were not altered following cisplatin treatment. Expression of other antiapoptotic members of the Bcl-2 family such as Bcl-2 and BclxL was not affected by cisplatin treatment. Cisplatin-induced loss of Mcl-1 occurs at the same time as the mitochondrial release of cytochrome c, activation of caspase-3, and initiation of apoptosis. Treatment of cells with cycloheximide, a protein synthesis inhibitor, revealed rapid turnover of Mcl-1. In addition, treatment with cycloheximide in the presence or absence of cisplatin demonstrated that cisplatin-induced loss of Mcl-1 results from posttranslational degradation rather than transcriptional inhibition. Overexpression of Mcl-1 protected cells from cisplatin-induced caspase-3 activation and apoptosis. Preincubating cells with the proteasome inhibitor MG-132 or lactacystin not only restored cisplatin-induced loss of Mcl-1 but also resulted in an accumulation of Mcl-1 that exceeded basal levels; however, Bcl-2 and BclxL levels did not change in response to MG-132 or lactacystin. The proteasome inhibitors effectively blocked cisplatin-induced mitochondrial release of cytochrome c, caspase-3 activation, and apoptosis. These studies suggest that proteasome regulation of Mcl-1 is crucial in the cisplatin-induced apoptosis via the mitochondrial apoptotic pathway and that Mcl-1 is an important therapeutic target in cisplatin injury to renal tubular epithelial cells.

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Insulin Inhibits Caspase-3 Activity in Human Renal Tubular Epithelial Cells via the PI3-Kinase/Akt Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000129386 ◽

2008 ◽

Vol 21 (4) ◽

pp. 279-286 ◽

Cited By ~ 8

Author(s):

Markus Meier ◽

Martin Nitschke ◽

Caroline Hocke ◽

Jan Kramer ◽

Wolfram Jabs ◽

...

Keyword(s):

Epithelial Cells ◽

Caspase 3 ◽

Pi3 Kinase ◽

Akt Pathway ◽

Tubular Epithelial Cells ◽

Renal Tubular Epithelial Cells ◽

Renal Tubular

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Aristolochic Acid I Induced Autophagy Extenuates Cell Apoptosis via ERK 1/2 Pathway in Renal Tubular Epithelial Cells

PLoS ONE ◽

10.1371/journal.pone.0030312 ◽

2012 ◽

Vol 7 (1) ◽

pp. e30312 ◽

Cited By ~ 50

Author(s):

Youjia Zeng ◽

Xiao Yang ◽

Juan Wang ◽

Jinjin Fan ◽

Qingyu Kong ◽

...

Keyword(s):

Epithelial Cells ◽

Cell Apoptosis ◽

Aristolochic Acid ◽

Tubular Epithelial Cells ◽

Renal Tubular Epithelial Cells ◽

Renal Tubular ◽

Aristolochic Acid I

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Caspase 3/GSDME-dependent pyroptosis contributes to chemotherapy drug-induced nephrotoxicity

Cell Death and Disease ◽

10.1038/s41419-021-03458-5 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Xiujin Shen ◽

Haibing Wang ◽

Chunhua Weng ◽

Hong Jiang ◽

Jianghua Chen

Keyword(s):

Epithelial Cells ◽

Caspase 3 ◽

Tubular Epithelial Cell ◽

Tubular Epithelial Cells ◽

Chemotherapeutic Drug ◽

Renal Tubular Epithelial Cells ◽

Renal Tubular Epithelial Cell ◽

Drug Induced ◽

Jnk Signaling ◽

Renal Tubular

AbstractChemotherapy drug-induced nephrotoxicity limits clinical applications for treating cancers. Pyroptosis, a newly discovered programmed cell death, was recently reported to be associated with kidney diseases. However, the role of pyroptosis in chemotherapeutic drug-induced nephrotoxicity has not been fully clarified. Herein, we demonstrate that the chemotherapeutic drug cisplatin or doxorubicin, induces the cleavage of gasdermin E (GSDME) in cultured human renal tubular epithelial cells, in a time- and concentration-dependent manner. Morphologically, cisplatin- or doxorubicin-treated renal tubular epithelial cells exhibit large bubbles emerging from the cell membrane. Furthermore, activation of caspase 3, not caspase 9, is associated with GSDME cleavage in cisplatin- or doxorubicin-treated renal tubular epithelial cells. Meanwhile, silencing GSDME alleviates cisplatin- or doxorubicin-induced HK-2 cell pyroptosis by increasing cell viability and decreasing LDH release. In addition, treatment with Ac-DMLD-CMK, a polypeptide targeting mouse caspase 3-Gsdme signaling, inhibits caspase 3 and Gsdme activation, alleviates the deterioration of kidney function, attenuates renal tubular epithelial cell injury, and reduces inflammatory cytokine secretion in vivo. Specifically, GSDME cleavage depends on ERK and JNK signaling. NAC, a reactive oxygen species (ROS) inhibitor, reduces GSDME cleavage through JNK signaling in human renal tubular epithelial cells. Thus, we speculate that renal tubular epithelial cell pyroptosis induced by chemotherapy drugs is mediated by ROS-JNK-caspase 3-GSDME signaling, implying that therapies targeting GSDME may prove efficacious in overcoming chemotherapeutic drug-induced nephrotoxicity.

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Effects and Mechanism of Salvianolic Acid B on the Injury of Human Renal Tubular Epithelial Cells Induced by Iopromide

Frontiers in Pharmacology ◽

10.3389/fphar.2021.761908 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shu-Jun Dong ◽

Xin-Yue Gao ◽

Ming-Xin Pei ◽

Ting Luo ◽

Dong Fan ◽

...

Keyword(s):

Epithelial Cells ◽

Serum Creatinine ◽

Cell Viability ◽

Caspase 3 ◽

Salvianolic Acid B ◽

Tubular Epithelial Cells ◽

Renal Tubular Epithelial Cells ◽

Absolute Increase ◽

Salvianolic Acid ◽

Renal Tubular

With the increasing application of medical imaging contrast materials, contrast-induced nephropathy (CIN) has become the third major cause of iatrogenic renal insufficiency. CIN is defined as an absolute increase in serum creatinine levels of at least 0.50 mg/dl or an increase >25% of serum creatinine from baseline after exposure to contrast. In this study, the protective effects of salvianolic acid B (Sal B) were detected in human renal tubular epithelial cells (HK-2) exposed to iopromide. The results showed that different concentrations of Sal B counteract the loss of cell viability induced by iopromide, and reduce cell apoptosis, the reactive oxygen species (ROS) levels, and the levels of endoplasmic reticulum stress (ERS)–related and apoptosis-related proteins such as p-IRE-1α, p-eIF-2α/eIF-2α, p-JNK, CHOP, Bax/Bcl-2, and cleaved caspase-3. In addition, Sal B at a concentration of 100 μmol/L inhibited ERS and reduced cell damage to a similar extent as the ERS inhibitor 4-PBA. Importantly, treatment with Sal B could abolish the injury induced by ERS agonist tunicamycin, increasing cell viability and the mitochondrial membrane potential, as well as significantly reducing ROS levels and the expression of Bax/Bcl-2, cleaved-caspase-3, GRP78, p-eIF2α, p-JNK, and CHOP. These results suggested that the protective effect of Sal B against HK-2 cell injury induced by iopromide may be related to the inhibition of ERS.

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