The endoplasmic reticulum (ER) stress mediated cell apoptotic pathway is down regulated in JNK1 and JNK3 knockout mice following kainic acid injection

Abstract Background and Aims Nephrotoxicity is an important cisplatin-induced adverse reaction and restricts the use of cisplatin to treat malignant tumors. Endoplasmic reticulum (ER) stress is caused by the accumulation of misfolded proteins, and is induced by cisplatin in kidneys. SIRT2 nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase is a member of the sirtuin family, but its role in cisplatin-induced ER stress remains unclear. Method To investigate the effect of SIRT2 on cisplatin-induced ER stress using SIRT2 knockout mice and human proximal tubular epithelial cells (HK-2 cells). We treated cisplatin (20 µg/mL) or induced by intraperitoneal injection of cisplatin (20 mg/kg) and evaluated the changes of ER stress and its signal mechanism. Results Cisplatin administration was found to significantly increase the expressions of PRKR-like ER kinase (PERK), phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), and the C/EBP homologous protein (CHOP) and caspase-12 in the kidneys of SIRT2-wild type mice. However, cisplatin-induced increases in the expressions of p-PERK, p-eIF2α, CHOP and, caspase-12 were diminished in kidneys of SIRT2 knockout mice. In vitro, cisplatin significantly increased the expressions of p-PERK, p-eIF2α, CHOP, and caspase-12 in HK-2 cells. When the effect of SIRT2 on cisplatin-induced ER stress was evaluated using SIRT2-siRNA (ON-TARGET plus human SIRT2 siRNA) or the SIRT2 inhibitors, AGK2 and AK1, knockdown or inhibition of SIRT2 significantly attenuated the cisplatin-induced protein expression of p-PERK, p-eIF2α, CHOP, and caspase-12. Immunoprecipitation studies showed SIRT2 bound physically to heat shock factor (HSF)1 and that HSF1 acetylation was significantly increased by cisplatin. In addition, knockdown of SIRT2 increased cisplatin-induced HSF1 acetylation and increased the expression of heat shock protein (HSP)70. Conclusion These observations suggest that suppression of SIRT2 ameliorates cisplatin-induced ER stress by increasing HSF1 acetylation and HSP expression.

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Ultrastructure of parvalbumin-immunoreactive neurons in the CA1 area of the rat hippocampus following a kainic acid injection

Acta Neuropathologica ◽

10.1007/bf00296189 ◽

1994 ◽

Vol 87 (2) ◽

pp. 187-195 ◽

Cited By ~ 29

Author(s):

N. Best ◽

J. Mitchell ◽

H. V. Wheal

Keyword(s):

Kainic Acid ◽

Rat Hippocampus ◽

Acid Injection ◽

Kainic Acid Injection ◽

Ca1 Area

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KAINIC ACID INJECTION IN NTS EVOKES HYPERTENSION AND C-FOS EXPRESSION IN SPINAL CORD

Neuroreport ◽

10.1097/00001756-199205000-00015 ◽

1992 ◽

Vol 3 (5) ◽

pp. 437-440 ◽

Cited By ~ 10

Author(s):

Jane Minson ◽

Vimal Kapoor ◽

Ida Llewellyn-Smith ◽

Paul Pilowsky ◽

John Chalmers

Keyword(s):

Spinal Cord ◽

Kainic Acid ◽

Acid Injection ◽

Fos Expression ◽

Kainic Acid Injection

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Ovarian steroid dependence of endoplasmic reticulum stress involvement in endometrial cell apoptosis during the human endometrial cycle

Reproduction ◽

10.1530/rep-17-0713 ◽

2018 ◽

Vol 155 (6) ◽

pp. 493-503 ◽

Cited By ~ 8

Author(s):

Jong Yeob Choi ◽

Min Wha Jo ◽

Eun Young Lee ◽

Dong-Yun Lee ◽

Doo Seok Choi

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Steroid Hormones ◽

Cellular Stress Response ◽

Apoptosis Induction ◽

Ovarian Steroid ◽

Secretory Phase ◽

Apoptotic Pathway ◽

Endometrial Cells ◽

Chop Expression

Endoplasmic reticulum (ER) stress is a common cellular stress response that enhances apoptosis to trigger cell death. However, recent studies have shown that estrogen suppresses apoptosis by inhibiting ER stress in some cell types, suggesting that ER stress-induced apoptosis is regulated by ovarian steroid hormones. In endometrial cells, ER stress may also be controlled by ovarian steroid hormones and could be involved in apoptosis induction during the menstrual cycle. To test this hypothesis, we elucidate whether ER stress is regulated by ovarian steroid hormones in human endometrial cells and if it is involved in apoptosis induction. Specifically, we sought to determine the effects of estrogen and progesterone on the PERK/eIF2α/ATF4/CHOP pathway, a pro-apoptotic pathway mediated by ER stress. Our results show that ER stress maker GRP78 expression was increased in human endometrial Ishikawa and endometrial stromal cells (ESCs) treated with tunicamycin. Addition of estrogen decreased tunicamycin-induced GRP78 expression. In contrast, progesterone treatment increased GRP78 in estrogen-treated Ishikawa and ESCs, which significantly increased CHOP expression through phosphorylation of eIF2α and upregulation of ATF4. This upregulation was accompanied by an increased apoptosis induction. The progesterone-induced increase in apoptosis was reversed by either mifepristone (progesterone receptor modulator) or salubrinal (ER stress inhibitor). Furthermore, our in vivo results also showed that GRP78, CHOP expression and apoptosis were significantly increased in endometrial cells during the secretory phase as well as by in vitro treatment with progesterone. In conclusion, our results suggest that estrogen inhibits ER stress in human endometrial cells. This inhibition is reversed by progesterone during the secretory phase, and this is directly involved in apoptosis induction.

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