Transglutaminase-1 protects renal epithelial cells from hydrogen peroxide-induced apoptosis through activation of STAT3 and AKT signaling pathways

Our recent studies showed that transglutaminase-1 (TGase-1) is uniquely expressed in mouse renal proximal tubular cells (RPTC) and mediates cell proliferation. In this study, we investigated the role of TGase-1 in cell survival and the survival signaling pathways regulated by TGase-1 in RPTC following oxidant injury. Exposure of RPTC to hydrogen peroxide (H2O2) resulted in apoptosis and an increase in TGase activity. Inhibition of TGase activity with monodansylcadervine (MDC), a TGase inhibitor, or knockdown of TGase-1 with small interference (si)RNA enhanced apoptosis and decreased cell survival in H2O2-treated RPTC. Conversely, overexpression of TGase-1 rendered RPTC more resistant to H2O2 toxicity and MDC treatment blocked this response. Concurrent with RPTC apoptosis, phosphorylation of AKT, signal transducer and activator of transcription-3 (STAT3), and glucogen synthase kinase-3β (GSK-3β) were observed. Pretreatment of cells with MDC or TGase-1 siRNA inhibited phosphorylation of all these molecules. Inhibition of either the AKT or STAT3 pathway potentiated H2O2-induced cell death and increased GSK-3β activity by dephosphorylation at serine 9. Furthermore, treatment with GSK-3β inhibitors reduced H2O2-induced apoptosis and abolished the death-promoting effect of AKT and STAT3 inhibition. Therefore, we have identified TGase-1 as a novel survival factor in renal epithelial cells and it contributes to cell survival through activation of the AKT and STAT3 signaling pathways following oxidant injury.

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EGFR-dependent ERK activation triggers hydrogen peroxide-induced apoptosis in OK renal epithelial cells

Archives of Toxicology ◽

10.1007/s00204-005-0052-2 ◽

2005 ◽

Vol 80 (6) ◽

pp. 337-346 ◽

Cited By ~ 25

Author(s):

Ju Suk Lee ◽

Su Yung Kim ◽

Chae Hwa Kwon ◽

Yong Keun Kim

Keyword(s):

Hydrogen Peroxide ◽

Epithelial Cells ◽

Erk Activation ◽

Renal Epithelial Cells ◽

Induced Apoptosis

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Super-resolution microscopy reveals that Na+/K+-ATPase signaling protects against glucose-induced apoptosis by deactivating Bad

Cell Death and Disease ◽

10.1038/s41419-021-04025-8 ◽

2021 ◽

Vol 12 (8) ◽

Author(s):

Kristoffer Bernhem ◽

Jacopo M. Fontana ◽

Daniel Svensson ◽

Liang Zhang ◽

Linnéa M. Nilsson ◽

...

Keyword(s):

Epithelial Cells ◽

Chronic Diseases ◽

Kidney Diseases ◽

Super Resolution ◽

Diabetic Patients ◽

Diabetic Kidney ◽

Renal Epithelial Cells ◽

Apoptotic Process ◽

Induced Apoptosis ◽

Super Resolution Microscopy

AbstractActivation of the apoptotic pathway is a major cause of progressive loss of function in chronic diseases such as neurodegenerative and diabetic kidney diseases. There is an unmet need for an anti-apoptotic drug that acts in the early stage of the apoptotic process. The multifunctional protein Na+,K+-ATPase has, in addition to its role as a transporter, a signaling function that is activated by its ligand, the cardiotonic steroid ouabain. Several lines of evidence suggest that sub-saturating concentrations of ouabain protect against apoptosis of renal epithelial cells, a common complication and major cause of death in diabetic patients. Here, we induced apoptosis in primary rat renal epithelial cells by exposing them to an elevated glucose concentration (20 mM) and visualized the early steps in the apoptotic process using super-resolution microscopy. Treatment with 10 nM ouabain interfered with the onset of the apoptotic process by inhibiting the activation of the BH3-only protein Bad and its translocation to mitochondria. This occurred before the pro-apoptotic protein Bax had been recruited to mitochondria. Two ouabain regulated and Akt activating Ca2+/calmodulin-dependent kinases were found to play an essential role in the ouabain anti-apoptotic effect. Our results set the stage for further exploration of ouabain as an anti-apoptotic drug in diabetic kidney disease as well as in other chronic diseases associated with excessive apoptosis.

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Involvement of endoplasmic reticulum stress-activated PERK-eIF2α-ATF4 signaling pathway in T-2 toxin-induced apoptosis of porcine renal epithelial cells

Toxicology and Applied Pharmacology ◽

10.1016/j.taap.2021.115753 ◽

2021 ◽

pp. 115753

Author(s):

Xiangyan Liu ◽

Ze Wang ◽

Xianglin Wang ◽

Xiaona Yan ◽

Qing He ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Epithelial Cells ◽

Endoplasmic Reticulum Stress ◽

Signaling Pathway ◽

Renal Epithelial Cells ◽

Induced Apoptosis

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ERK promotes hydrogen peroxide-induced apoptosis through caspase-3 activation and inhibition of Akt in renal epithelial cells

AJP Renal Physiology ◽

10.1152/ajprenal.00170.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. F440-F447 ◽

Cited By ~ 100

Author(s):

Shougang Zhuang ◽

Yan Yan ◽

Rebecca A. Daubert ◽

Jiahuai Han ◽

Rick G. Schnellmann

Keyword(s):

Hydrogen Peroxide ◽

Epithelial Cells ◽

Caspase 3 ◽

Ischemia Reperfusion ◽

Nuclear Condensation ◽

Histone H2b ◽

Adenoviral Infection ◽

Akt Phosphorylation ◽

Renal Proximal Tubular Cells ◽

Induced Apoptosis

Reactive oxygen species, including hydrogen peroxide (H2O2), are generated during ischemia-reperfusion and are critically involved in acute renal failure. The present studies examined the role of the extracellular signal-regulated kinase (ERK) pathway in H2O2-induced renal proximal tubular cells (RPTC) apoptosis. Exposure of RPTC to 1 mM H2O2resulted in apoptosis and activation of ERK1/2 and Akt. Pretreatment with the specific MEK inhibitors, U0126 and PD98059, or adenoviral infection with a construct that encodes a negative mutant of MEK1, protected cells against H2O2-induced apoptosis. In contrast, expression of constitutively active MEK1 enhanced H2O2-induced apoptosis. H2O2induced activation of caspase-3 and phosphorylation of histone H2B at serine 14, a posttranslational modification required for nuclear condensation, which also were blocked by ERK1/2 inhibition. Furthermore, blockade of ERK1/2 resulted in an increase in Akt phosphorylation and blockade of Akt potentiated apoptosis and diminished the protective effect conferred by ERK inhibition in H2O2-treated cells. Although Z-DEVD-FMK, a caspase-3 inhibitor, was able to inhibit histone H2B phosphorylation and apoptosis, it did not affect ERK1/2 phosphorylation. We suggest that ERK elicits apoptosis in epithelial cells by activating caspase-3 and inhibiting Akt pathways and elicits nuclear condensation through caspase-3 and histone H2B phosophorylation during oxidant injury.

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