Cadmium induces triglyceride levels via microsomal triglyceride transfer protein (MTTP) accumulation caused by lysosomal deacidification regulated by endoplasmic reticulum (ER) Ca2+ homeostasis

Kong, Anqi; Zhang, Yao; Niu, Bo; Li, Kongdong; Ren, Zhen; Dai, Shengping; Chen, Dongfeng; Zhou, Yang; Gu, Jie; Shi, Haifeng

doi:10.1016/j.cbi.2021.109649

Cited by 10 publications

(5 citation statements)

References 68 publications

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“…In the primary culture of rat cerebral cortical neurons, Cd 2+ induced apoptosis by inhibiting Ca 2+ -ATPase activity [ 30 ]. In HepG2 cells, SERCA agonist CDN1163 can reverse Cd 2+ -increased triglyceride levels [ 31 ]. The SERCA pump activity is regulated by phospholamban (PLB).…”

Section: Discussionmentioning

confidence: 99%

“…SERCA inhibitor Saikosaponin-D can inhibit the proliferation of autosomal dominant polycystic kidney disease (ADPKD) cells by promoting autophagy [ 38 ]. In liver HepG2 cells, the IP 3 R inhibitor 2-APB could restore the Cd 2+ -disrupted lysosomal acidic environment, which was also dysregulated by SERCA inhibitor TG [ 31 ]. Here, our result also confirms that TG treatment inhibits the autophagy flux as p62 accumulates in renal tubular cells.…”

Section: Discussionmentioning

confidence: 99%

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Cadmium Disrupted ER Ca2+ Homeostasis by Inhibiting SERCA2 Expression and Activity to Induce Apoptosis in Renal Proximal Tubular Cells

Guo

Ruan

et al. 2023

IJMS

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Cadmium (Cd2+) exposure induces chronic kidney disease and renal cancers, which originate from injury and cancerization of renal tubular cells. Previous studies have shown that Cd2+ induced cytotoxicity by disrupting the intracellular Ca2+ homeostasis that is physically regulated by the endoplasmic reticulum (ER) Ca2+ store. However, the molecular mechanism of ER Ca2+ homeostasis in Cd2+-induced nephrotoxicity remains unclear. In this study, our results firstly revealed that the activation of calcium-sensing receptor (CaSR) by NPS R-467 could protect against Cd2+ exposure-induced cytotoxicity of mouse renal tubular cells (mRTEC) by restoring ER Ca2+ homeostasis through the ER Ca2+ reuptake channel sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). Cd2+-induced ER stress and cell apoptosis were effectively abrogated by SERCA agonist CDN1163 and SERCA2 overexpression. In addition, in vivo, and in vitro results proved that Cd2+ reduced the expressions of SERCA2 and its activity regulator phosphorylation phospholamban (p-PLB) in renal tubular cells. Cd2+-induced SERCA2 degradation was suppressed by the treatment of proteasome inhibitor MG132, which suggested that Cd2+ reduced SERCA2 protein stability by promoting the proteasomal protein degradation pathway. These results suggested that SERCA2 played pivotal roles in Cd2+-induced ER Ca2+ imbalance and stress to contribute to apoptosis of renal tubular cells, and the proteasomal pathway was involved in regulating SERCA2 stability. Our results proposed a new therapeutic approach targeting SERCA2 and associated proteasome that might protect against Cd2+-induced cytotoxicity and renal injury.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cadmium Disrupted ER Ca2+ Homeostasis by Inhibiting SERCA2 Expression and Activity to Induce Apoptosis in Renal Proximal Tubular Cells

Guo

Ruan

et al. 2023

IJMS

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“…In hepatic cell HepG2, Cd induced Ca 2+ release from the ER store to the cytosol, which caused disruption of the lysosomal acidic environment, resulting in degradation. However, the Cd-disrupted lysosomal pH was restored by pretreatment with the IP3R inhibitor 2-APB and the SERCA activator CDN1163 [62,63]. This suggests that Ca 2+ mediates interaction between the ER and mitochondria and lysosomes, and modulates lysosomal function.…”

Section: Lysosomal Ca 2+ Signaling In Kidney Diseasesmentioning

confidence: 99%

Calcium Signaling Mediates Cell Death and Crosstalk with Autophagy in Kidney Disease

Niu

Guo

Kong

et al. 2021

Cells

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The kidney is an important organ for the maintenance of Ca2+ homeostasis in the body. However, disruption of Ca2+ homeostasis will cause a series of kidney diseases, such as acute kidney injury (AKI), chronic kidney disease (CKD), renal ischemia/reperfusion (I/R) injury, autosomal dominant polycystic kidney disease (ADPKD), podocytopathy, and diabetic nephropathy. During the progression of kidney disease, Ca2+ signaling plays key roles in various cell activities such as necrosis, apoptosis, eryptosis and autophagy. Importantly, there are complex Ca2+ flux networks between the endoplasmic reticulum (ER), mitochondria and lysosomes which regulate intracellular Ca2+ signaling in renal cells and contribute to kidney disease. In addition, Ca2+ signaling also links the crosstalk between various cell deaths and autophagy under the stress of heavy metals or high glucose. In this regard, we present a review of Ca2+ signaling in cell death and crosstalk with autophagy and its potential as a therapeutic target for the development of new and efficient drugs against kidney diseases.

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“…Ca 2+ uptake by lysosomes may regulate lysosomal pH due to the activation of a lysosomal Ca 2+ /H + exchanger ( Figure 1 A). For example, in hepatic cell HepG2, Ca 2+ release from the ER caused a disruption of the lysosomal acidity and impaired protein degradation [ 99 ]. Recently increased Ca 2+ release via RyanRs was reported to be associated with reduced expression of the lysosome proton pump vacuolar-ATPase (vATPase) subunits (V1B2 and V0a1), which cause lysosome deacidification and disrupt proteolytic activity.…”

Section: Dysregulated Ca 2+ Signaling and Autophag...mentioning

confidence: 99%

“…( A ) Supranormal RyanR-mediated Ca 2+ release in AD neurons may decrease lysosomal vATPase expression levels through post-translational modifications that affect its assembly and insertion to the lysosome or disrupts vATPase function through stimulation of lysosomal Ca 2+ /H + exchangers. Based on [ 24 , 99 ]. ( B ) Presenilin 1 (PS1) knockout or FAD linked mutations in PS1 lead to impaired glycosylation and instability of vATPase V0a1 subunit, further induce deficient lysosomal vATPase assembly and impaired its function and elevated lysosomal pH.…”

Section: Figurementioning

confidence: 99%

“Dirty Dancing” of Calcium and Autophagy in Alzheimer’s Disease

Zhang

Bezprozvanny

2023

Life

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Alzheimer’s disease (AD) is the most common cause of dementia. There is a growing body of evidence that dysregulation in neuronal calcium (Ca2+) signaling plays a major role in the initiation of AD pathogenesis. In particular, it is well established that Ryanodine receptor (RyanR) expression levels are increased in AD neurons and Ca2+ release via RyanRs is augmented in AD neurons. Autophagy is important for removing unnecessary or dysfunctional components and long-lived protein aggregates, and autophagy impairment in AD neurons has been extensively reported. In this review we discuss recent results that suggest a causal link between intracellular Ca2+ signaling and lysosomal/autophagic dysregulation. These new results offer novel mechanistic insight into AD pathogenesis and may potentially lead to identification of novel therapeutic targets for treating AD and possibly other neurodegenerative disorders.

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Cadmium induces triglyceride levels via microsomal triglyceride transfer protein (MTTP) accumulation caused by lysosomal deacidification regulated by endoplasmic reticulum (ER) Ca2+ homeostasis

Cited by 10 publications

References 68 publications

Cadmium Disrupted ER Ca2+ Homeostasis by Inhibiting SERCA2 Expression and Activity to Induce Apoptosis in Renal Proximal Tubular Cells

Cadmium Disrupted ER Ca2+ Homeostasis by Inhibiting SERCA2 Expression and Activity to Induce Apoptosis in Renal Proximal Tubular Cells

Calcium Signaling Mediates Cell Death and Crosstalk with Autophagy in Kidney Disease

“Dirty Dancing” of Calcium and Autophagy in Alzheimer’s Disease

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