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

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) ? 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 TGF?1-dependent Smad3 phosphorylation. Furthermore, ALK4/5 signaling activated Akt signaling to promote cadmium-induced HK-2 cell death. In contrast, siRNA-mediated Inhibin-bA silencing or treatment with TGF?1 or activin A had little effect on cadmium-induced HK-2 cell death. On the other hand, treatment with SB431542 or SB505124 attenuated erastin-induced ferroptosis by hyperactivating Nrf2 signaling in HK-2 cells. These results suggest that blockade of ALK4/5 signaling protects against cadmium- and erastin-induced HK-2 cell death via Akt and Nrf2 signaling pathways, respectively.

SUBMITTER: Fujiki K

PROVIDER: S-EPMC6889492 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Fujiki Kota K Inamura Hisako H Sugaya Takeshi T Matsuoka Masato M

Cell death and differentiation 20190225 11

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 grow ...[more]

PMID: 30804470

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Project description:We examined the roles of Notch1 signaling and its cross-talk with other signaling pathways, including p53 and phosphatidylinositol-3-kinase (PI3K)/Akt, in cadmium-induced cellular damage in HK-2 human renal proximal tubular epithelial cells. Following exposure to cadmium chloride (CdCl2), the level of Notch intracellular domain (NICD), the cleaved form of the Notch1 receptor, was increased and accumulated in the nuclear fraction. Knockdown of Notch1 with siRNA or treatment with the ?-secretase inhibitor, DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester), prevented CdCl2-induced morphological change of HK-2 cells and reduction of cell viability. Knockdown of Jagged1 or Jagged2, the ligands of the Notch1 receptor, partially suppressed cadmium cytotoxicity. Inhibition of p53 activity with pifithrin-? or inhibition of PI3K with LY294002 suppressed CdCl2-induced cellular damage and elevation of Notch1-NICD. In addition, treatment with the epidermal growth factor receptor (EGFR) inhibitor, AG1478, and the insulin-like growth factor-1 receptor inhibitor, PPP, suppressed both Notch1-NICD accumulation and Akt phosphorylation in HK-2 cells exposed to CdCl2. However, knockdown of Notch1 did not affect CdCl2-induced p53 accumulation and phosphorylation but suppressed phosphorylation of EGFR, Akt, and p70 S6 kinase. Depletion of Notch1 suppressed CdCl2-induced reduction of E-cadherin expression and elevation of Snail expression. Furthermore, treatment with SB216763, an inhibitor of glycogen synthase kinase-3, suppressed the potency of LY294002 treatment to reduce Snail expression in HK-2 cells exposed to CdCl2. Knockdown of Snail with siRNA partially prevented HK-2 cells from CdCl2-induced reduction of E-cadherin expression and cellular damage. These results suggest that cadmium exposure induces the activation of Notch1 signaling in renal proximal tubular cells with cooperative activation by the p53 and PI3K/Akt signaling pathways; the resultant expression of Snail, a repressor of E-cadherin expression, might lead to cellular damage by decreasing cell-cell adhesion.

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

Publications

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

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