Blockade of ALK4/5 signaling suppresses cadmium- and erastin-induced cell death in renal proximal tubular epithelial cells via distinct signaling mechanisms

Cell Death and Differentiation
Kota FujikiMasato Matsuoka

Abstract

Various types of cell death, including apoptosis, necrosis, necroptosis, and ferroptosis, are induced in renal tubular epithelial cells following exposure to environmental stresses and toxicants such as osmotic stress, ischemia/reperfusion injury, cisplatin, and cadmium. This is known to cause renal dysfunction, but the cellular events preceding stress-induced cell death in renal tubules are not fully elucidated. The activin receptor-like kinase (ALK) 4/5, also known as activin-transforming growth factor (TGF) β receptor, is involved in stress-induced renal injury. We, therefore, studied the role of ALK4/5 signaling in HK-2 human proximal tubular epithelial cell death induced by cisplatin, cadmium, hyperosmotic stress inducer, sorbitol, and the ferroptosis activator, erastin. We found that ALK4/5 signaling is involved in cadmium- and erastin-induced cell death, but not sorbitol- or cisplatin-induced apoptotic cell death. Cadmium exposure elevated the level of phosphorylated Smad3, and treatment with the ALK4/5 kinase inhibitors, SB431542 or SB505124, suppressed cadmium-induced HK-2 cell death. Cadmium-induced cell death was attenuated by siRNA-mediated ALK4 or Smad3 silencing, or by treatment with SIS3, a selective inhibitor of...Continue Reading

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Citations

Dec 2, 2019·Biological Trace Element Research·Milad AshrafizadehSaeed Samarghandian
Jan 22, 2020·American Journal of Physiology. Endocrinology and Metabolism·Fuxin WangPeter C K Leung
Apr 6, 2019·Cell Research·Daolin TangGuido Kroemer
Mar 18, 2021·Journal of Oncology·Xiaotao JiangKunhai Zhuang
Jun 5, 2021·Frontiers in Pharmacology·Lise VerbruggenAnn Massie
Aug 18, 2021·Ecotoxicology and Environmental Safety·Peixian LuanZiwei Zhang

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Methods Mentioned

BETA
environmental stresses
ELISA
Protein Assay
electrophoresis
enzyme-linked immunosorbent assay
reverse transcription-PCR

Related Concepts

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Apoptosis

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