Cadmium induces the expression of Interleukin-6 through Heme Oxygenase-1 in HK-2 cells and Sprague-Dawley rats. (March 2022)

• Record Type: Journal Article
• Authors: Ou, Yen-Chuan; Li, Jian-Ri; Wu, Chih-Cheng; Yu, Tung-Min; Chen, Wen-Ying; Liao, Su-Lan; Kuan, Yu-Hsiang; Chen, Yu-Fan; Chen, Chun-Jung
• Is Part Of: Food and chemical toxicology. Volume 161(2022)
• Publication Date: 2022-03
• Subjects: Cadmium -- Heme oxygenase 1 -- Interleukin-6 -- Nephrotoxicity -- Reactive oxygen species; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2022.112846
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Cadmium is toxic to the kidney through mechanisms involving oxidative stress and inflammation. We studied reciprocal crosstalk among the oxidative stress, inflammation, and the nuclear Nrf2 pathway in cadmium-induced nephrotoxicity on HK-2 human renal proximal tubular epithelial cells. Cadmium chloride (CdCl2 ) caused cell viability loss, Reactive Oxygen Species (ROS) generation, glutathione reduction, and Interleukin-6 (IL-6) expression, accompanied by Nrf2 activation and Heme Oxygenase-1 (HO-1) expression. Pharmacological treatments demonstrated cytotprotective and anti-inflammatory effects of Nrf2 activation. Intriguingly, inhibition of HO-1 activity mitigated cell viability loss and IL-6 expression in CdCl2 -treated cells. Parallel attenuation by HO-1 inhibitor was demonstrated in cadmium-induced ROS generation and glutathione reduction. CdCl2 -treated cells also increased levels of ferrous iron, cGMP, Mitogen-Activated Protein Kinases phosphorylation, as well as NF-κB DNA-binding activity. These increments were mitigated by antioxidant N-Acetyl Cysteine, HO-1 inhibitor SnPP, and PKG inhibitor KT5823, and were mimicked by the Carbon Monoxide-releasing compound. In the kidney cortex of CdCl2 -exposed Sprague-Dawley rats, we found similar renal injury, histological changes, ROS generation, IL-6 expression, and accompanied pro-oxidant and pro-inflammatory changes. These observations indicated that cadmium-induced nephrotoxicity was associated with oxidative stress and inflammation, and HO-1 likely acts as a linking molecule to induce nephrotoxicity-associated IL-6 expression upon cadmium exposure. Graphical abstract: Image 1 Highlights: Cadmium causes oxidative stress and IL-6 expression in HK-2 cells and kidney of exposed rats. Cadmium induces Nrf2 and HO-1 activation. Nrf2 activation decreases cadmium-induced cell injury and IL-6 expression. The HO-1/CO/sGC/cGMP/PKG/MAPKs/NF-κB axes contribute to cadmium-induced IL-6 expression.