Inhibition of Starvation-Triggered Endoplasmic Reticulum Stress, Autophagy, and Apoptosis in ARPE-19 Cells by Taurine through Modulating the Expression of Calpain-1 and Calpain-2

Zhang, Yuanyuan; Ren, Shu; Liu, Yuci; Gao, Kun; Liu, Zheng; Zhou, Zhen

doi:10.3390/ijms18102146

Cited by 48 publications

(44 citation statements)

References 58 publications

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“…GRP78 and GRP94 expression was detected in our study in PAN nephrotic rats, which agrees with the findings that were reported by Inagi et al [ 19 ]. However, TAU preconditioning inhibited ER stress in nephrotic glomeruli and proximal tubules in line with previous studies on cisplatin or starvation-triggered ER damage [ 66 , 67 ].…”

Section: Discussionsupporting

confidence: 89%

Taurine Supplementation Alleviates Puromycin Aminonucleoside Damage by Modulating Endoplasmic Reticulum Stress and Mitochondrial-Related Apoptosis in Rat Kidney

et al. 2018

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Taurine (TAU) is a sulfur-containing beta amino acid that is not involved in protein composition and anabolism, conditionally essential in mammals provided through diet. Growing evidence supports a protective role of TAU supply in osmoregulation, calcium flux, and reduction of inflammation and oxidant damage in renal diseases like diabetes. Endoplasmic reticulum (ER) stress, due to abnormal proteostasis, is a contributor to nephrotic syndrome and related renal damage. Here, we investigated the effect of dietary TAU (1.5% in drinking water for 15 days) in an established rat model that mimics human minimal change nephrosis, consisting of a single puromycin aminonucleoside (PAN) injection (intraperitoneally 15 mg/100 g body weight), with sacrifice after eight days. TAU limited proteinuria and podocytes foot processes effacement, and balanced slit diaphragm nephrin and glomerular claudin 1 expressions. In cortical proximal tubules, TAU improved lysosomal density, ER perimeter, restored proper ER-mitochondria tethering and mitochondrial cristae, and decreased inflammation. Remarkably, TAU downregulated glomerular ER stress markers (GRP78, GRP94), pro-apoptotic C/EBP homologous protein, activated caspase 3, tubular caspase1, and mitochondrial chaperone GRP75, but maintained anti-apoptotic HSP25. In conclusion, TAU, by targeting upstream ER stress separate from mitochondria dysfunctions at crucial renal sites, might be a promising dietary supplement in the treatment of the drug-resistant nephrotic syndrome.

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Section: Discussionsupporting

confidence: 89%

Taurine Supplementation Alleviates Puromycin Aminonucleoside Damage by Modulating Endoplasmic Reticulum Stress and Mitochondrial-Related Apoptosis in Rat Kidney

et al. 2018

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“…Cells were serum-starved (SS) to induce stress (Fig. S5A,B) [63][64][65] and, consistent with our findings in animal and human tissues, cells showed increased PC2 mRNA and protein expression following serum starvation (Fig. 5A-C, S5A,C) and treatment with tunicamycin (TM), an inducer of ER stress (Fig.…”

Section: Pc2 Up-regulation Protects Cells Against Stress-induced Cellsupporting

confidence: 65%

Polycystin 2 is increased in disease to protect against stress-induced cell death

Brill

Fischer

Walters

et al. 2020

Sci Rep

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Polycystin 2 (PC2 or TRPP1, formerly TRPP2) is a calcium-permeant Transient Receptor Potential (TRP) cation channel expressed primarily on the endoplasmic reticulum (ER) membrane and primary cilia of all cell and tissue types. Despite its ubiquitous expression throughout the body, studies of PC2 have focused primarily on its role in the kidney, as mutations in PC2 lead to the development of autosomal dominant polycystic kidney disease (ADPKD), a debilitating condition for which there is no cure. However, the endogenous role that PC2 plays in the regulation of general cellular homeostasis remains unclear. In this study, we measure how PC2 expression changes in different pathological states, determine that its abundance is increased under conditions of cellular stress in multiple tissues including human disease, and conclude that PC2-deficient cells have increased susceptibility to cell death induced by stress. Our results offer new insight into the normal function of PC2 as a ubiquitous stress-sensitive protein whose expression is up-regulated in response to cell stress to protect against pathological cell death in multiple diseases. Polycystin-2 (PC2 or TRPP1, formerly TRPP2) is a Transient Receptor Potential (TRP) channel most well-known for its associated pathology. When mutated, PC2 causes autosomal dominant polycystic kidney disease (ADPKD), a debilitating condition leading to bilateral renal cyst formation and eventual kidney failure 1. Located primarily on the endoplasmic reticulum (ER) and primary cilia of all cell and tissue types 2-5 , PC2 is a calcium (Ca 2+)-permeant cation channel whose expression level directly affects Ca 2+ release from the ER 5. As such, PC2 is thought to play a key role in regulating Ca 2+-regulated homeostasis and signaling pathways 6. This is supported by findings showing that polycystin-deficient cells exhibit dysregulated Ca 2+ mobilization and Ca 2+-regulated signaling pathways 5,7 , including pathologically increased cAMP levels 8,9 and changes in mitochondrial Ca 2+ uptake 10,11. The aberrant Ca 2+ signaling caused by loss of polycystins is therefore often pointed to as a central cause of enhanced apoptosis 12,13 , excess fluid secretion 14,15 , and metabolic abnormalities 10,11,16-18 seen in cystic kidney cells. Given the importance of PC2 in ADPKD development, most studies of PC2 have focused on its function in the kidney. However, the ubiquitous expression of PC2 in all cell types suggests that it is important in maintaining Ca 2+ homeostasis in tissues beyond the kidney. The tight regulation of intracellular Ca 2+ is necessary for many physiological functions, including protecting cells against outside stressors. Oxidative and ER stress responses require Ca 2+ influx from both the extracellular

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“…Calcium/calmodulin-dependent kinase II can activate NOX5 via direct phosphorylation [ 15 ]. Moreover, some studies show that crosstalk between ROS and calpain leads to the release of Ca 2+ [ 24 – 27 ]. The nuclear translocation of calpain-2 can be activated by increased NOX-derived ROS.…”

Section: Introductionmentioning

confidence: 99%

“…In our previous study, we demonstrated that taurine inhibited starvation-triggered cell damage in ARPE-19 cells [ 24 ]. However, the detailed roles of NOX (one of the main ROS sources) in EBSS-induced cell injury remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Taurine Attenuates Calpain‐2 Induction and a Series of Cell Damage via Suppression of NOX‐Derived ROS in ARPE‐19 Cells

Zhang

Ren

et al. 2018

Oxidative Medicine and Cellular Longevity

Self Cite

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Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are key transmembrane proteins leading to reactive oxygen species (ROS) overproduction. However, the detailed roles of NOXs in retinal pigment epithelial (RPE) cell metabolic stress induced by Earle's balanced salt solution (EBSS) through starvation remain unclear. In this study, we investigated what roles NOXs play in regard to calpain activity, endoplasmic stress (ER), autophagy, and apoptosis during metabolic stress in ARPE-19 cells. We first found that EBSS induced an increase in NOX2, NOX4, p22phox, and NOX5 compared to NOX1. Secondly, suppression of NOXs resulted in reduced ER stress and autophagy, decreased ROS generation, and alleviated cell apoptosis. Thirdly, silencing of NOX4, NOX5, and p22phox resulted in reduced levels of cell damage. However, silencing of NOX1 was unaffected. Finally, taurine critically mediated NOXs in response to EBSS stress. In conclusion, this study demonstrated for the first time that NOX oxidases are the upstream regulators of calpain-2, ER stress, autophagy, and apoptosis. Furthermore, the protective effect of taurine is mediated by the reduction of NOX-derived ROS, leading to sequential suppression of calpain induction, ER stress, autophagy, and apoptosis.

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Inhibition of Starvation-Triggered Endoplasmic Reticulum Stress, Autophagy, and Apoptosis in ARPE-19 Cells by Taurine through Modulating the Expression of Calpain-1 and Calpain-2

Cited by 48 publications

References 58 publications

Taurine Supplementation Alleviates Puromycin Aminonucleoside Damage by Modulating Endoplasmic Reticulum Stress and Mitochondrial-Related Apoptosis in Rat Kidney

Taurine Supplementation Alleviates Puromycin Aminonucleoside Damage by Modulating Endoplasmic Reticulum Stress and Mitochondrial-Related Apoptosis in Rat Kidney

Polycystin 2 is increased in disease to protect against stress-induced cell death

Taurine Attenuates Calpain‐2 Induction and a Series of Cell Damage via Suppression of NOX‐Derived ROS in ARPE‐19 Cells

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