Cadmium exposure induces autophagy via PLC‐IP 3 ‐IP 3 R signaling pathway in duck renal tubular epithelial cells

Self Cite

Excess molybdenum (Mo) is harmful to animals, but its nephrotoxicity has not been comprehensively explained. To appraise the influences of excess Mo on Ca homeostasis and apoptosis via PLC/IP3/IP3R axis, primary duck renal tubular epithelial cells were exposed to 480 μM and 960 μM Mo, and joint of 960 μM Mo and 10 μM 2‐APB or 0.125 μM U‐73122 for 12 h (U‐73122 pretreated for 1 h), respectively. The data revealed that the increment of [Ca2+]c induced by Mo mainly originated from intracellular Ca storage. Mo exposure reduced [Ca2+]ER, elevated [Ca2+]mit, [Ca2+]c, and the expression of Ca homeostasis‐related factors (Calpain, CaN, CRT, GRP94, GRP78 and CaMKII). 2‐APB could effectively reverse subcellular Ca2+ redistribution by inhibiting IP3R, which confirmed that [Ca2+]c overload induced by Mo originated from ER. Additionally, PLC inhibitor U‐73122 remarkably mitigated the change, and dramatically reduced the number of apoptotic cells, the expression of Bak‐1, Bax, cleaved‐Caspase‐3/Caspase‐3, and notably increased the expression of Bcl‐xL, Bcl‐2, and Bcl‐2/Bax ratio. Overall, the results confirmed that the Ca2+ liberation of ER via PLC/IP3/IP3R axis was the main cause of [Ca2+]c overload, and then stimulated apoptosis in duck renal tubular epithelial cells.

Section: Methodsmentioning

confidence: 99%

Role of PLC/IP₃/IP₃R axis in excess molybdenum exposure induced apoptosis in duck renal tubular epithelial cells

Guo,

Zhang,

et al. 2023

Self Cite

“…7 The kidney, testicle, ovary, and heart are the primary organs damaged by Mo toxicity. 8,9 Study has shown that high concentrations of Mo can significantly reduce glutathione peroxidase (GSH-px) and glutathione (GSH) activities and Bingyan Huang and Gaohui Nie contributed equally as first authors.…”

Section: Introductionmentioning

confidence: 99%

“…The wide usage of Mo in industry and exploitation of Mo‐bearing mineral resources have largely augmented hazard of human beings and animals exposed to excess Mo 7 . The kidney, testicle, ovary, and heart are the primary organs damaged by Mo toxicity 8,9 . Study has shown that high concentrations of Mo can significantly reduce glutathione peroxidase (GSH‐px) and glutathione (GSH) activities and increase malondialdehyde (MDA) content, and then aggravate occurrence of lipid peroxidation (LPO) in the body, ultimately causing damage to organisms 10 .…”

Section: Introductionmentioning

confidence: 99%

Environmentally relevant levels of Cd and Mo coexposure induces ferroptosis and excess ferritinophagy through AMPK/mTOR axis in duck myocardium

Huang,

Nie,

Dai

et al. 2024

Self Cite

Cadmium (Cd) and excess molybdenum (Mo) are multiorgan toxic, but the detrimental impacts of Cd and/or Mo on poultry have not been fully clarified. Thence, a 16‐week sub‐chronic toxic experiment was executed with ducks to assess the toxicity of Cd and/or Mo. Our data substantiated that Cd and Mo coexposure evidently reduced GSH‐Px, GSH, T‐SOD, and CAT activities and elevated H2O2 and MDA concentrations in myocardium. What is more, the study suggested that Cd and Mo united exposure synergistically elevated Fe2+ content in myocardium and activated AMPK/mTOR axis, then induced ferroptosis by obviously upregulating ACSL4, PTGS2, and TFRC expression levels and downregulating SLC7A11, GPX4, FPN1, FTL1, and FTH1 expression levels. Additionally, Cd and Mo coexposure further caused excessive ferritinophagy by observably increasing autophagosomes, the colocalization of endogenous FTH1 and LC3, ATG5, ATG7, LC3II/LC3I, NCOA4, and FTH1 expression levels. In brief, this study for the first time substantiated that Cd and Mo united exposure synergistically induced ferroptosis and excess ferritinophagy by AMPK/mTOR axis, finally augmenting myocardium injure in ducks, which will offer an additional view on united toxicity between two heavy metals on poultry.

“…Acute kidney injury (AKI) is a common disease involving an acute decrease in kidney function, which may progress into chronic renal diseases and have a long‐term impact on human health. Increasing studies have found that environmental pollutant exposure is associated with AKI 1,2 . Cadmium (Cd) is a widespread pollutant and produces kidney injury upon long‐term low or short‐term high exposure due to its high affinity for metallothionine (MT) or other circulating proteins that can accumulate in the nephron, to eventually damage renal proximal tubule cells 3 .…”

Section: Introductionmentioning

confidence: 99%

“…Increasing studies have found that environmental pollutant exposure is associated with AKI. 1,2 Cadmium (Cd) is a widespread pollutant and produces kidney injury upon long-term low or short-term high exposure due to its high affinity for metallothionine (MT) or other circulating proteins that can accumulate in the nephron, to eventually damage renal proximal tubule cells. 3 2,2 0 ,4,4 0 -Tetrabromodiphenyl ether (BDE-47) as the most commonly used brominated flame retardant (BFR) is ubiquitous in the environment.…”

Section: Introductionmentioning

confidence: 99%

Cadmium (Cd) and 2,2′,4,4′‐tetrabromodiphenyl ether (BDE‐47) co‐exposure induces acute kidney injury through oxidative stress and RIPK3‐dependent necroptosis

Tang

Zhang

Chen

et al. 2023

Environmental pollution is complex, and co‐exposure can accurately reflect the true environmental conditions that are important for assessment of human health. Cadmium (Cd) is a widespread toxicant that can cause acute kidney injury (AKI), while its combined effect with 2,2′,4,4′‐tetrabromodiphenyl ether (BDE‐47) is not fully understood. Thus, we used an in vivo model where C57BL/6J mice were treated with low dietary intake of Cd (5 mg/kg/day) and/or BDE‐47 (1 mg/kg/day) for 28 days to examine AKI, and in vitro experiments to investigate the possible mechanism. Results showed that Cd or BDE‐47 caused pathological kidney damage, accompanied by elevated urea nitrogen (BUN) and urinary creatinine, as well as increased interleukin‐1β (IL‐1β) and tumor necrosis factor‐α (TNF‐α), and reduced IL‐10 in kidney tissues. In vitro Cd or BDE‐47 exposure decreased cell viability and induced cell swelling and blebbing of human embryonic kidney 293 (HEK‐293) and renal tubular epithelial cell lines (HKCs), and changes in co‐exposure was larger than that in Cd and BDE‐47 treatment. Oxidative stress indicators of the reactive oxygen species (ROS) and malondialdehyde (MDA) were elevated, while the antioxidant superoxide dismutase (SOD) was decreased. Necrosis occurred with increased lactate dehydrogenase (LDH) release and propidium iodide (PI) staining, which was attenuated by the ROS scavenger N‐acetyl‐L‐cysteine (NAC). Furthermore, necroptotic genes of receptor‐interacting protein kinase‐3 (RIPK3), classical mixed lineage kinase domain‐like protein‐dependent (MLKL), IL‐1β and TNF‐α were up‐regulated, whereas RIPK1 was down‐regulated, which was attenuated by the RIPK3 inhibitor GSK872. These findings demonstrate that Cd or BDE‐47 alone produces kidney toxicities, and co‐exposure poses an additive effect, resulting in AKI via inducing oxidative stress and regulating RIPK3‐dependent necroptosis, which offers a further mechanistic understanding for kidney damage, and the combined effect of environmental pollutants should be noticed.