Persistent activation of Nrf2 promotes a vicious cycle of oxidative stress and autophagy inhibition in cadmium-induced kidney injury

• Published in: Toxicology (Amsterdam) Vol. 464; p. 152999
• Main Authors: Fan, Rui-Feng, Tang, Kou-Kou, Wang, Zhen-Yong, Wang, Lin
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.12.2021
• Subjects: Animals; Antioxidants - metabolism; Autophagy; Autophagy - drug effects; Cadmium; Cadmium Chloride - toxicity; Cell Line; Gene Knockdown Techniques; Gene Silencing; Kidney Diseases - chemically induced; Kidney Diseases - pathology; Lysosome; Lysosomes - metabolism; Male; Nephrotoxicity; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nrf2; Oxidative stress; Oxidative Stress - drug effects; Rats; Rats, Sprague-Dawley; Cadmium; Oxidative stress; Nrf2; Autophagy; Nephrotoxicity; Lysosome
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2021.152999

Nuclear factor erythroid 2-related factor 2 (Nrf2) serves as the master regulator of antioxidant signaling and inhibition or hyperactivation of Nrf2 pathway will result in the redox imbalance to induce tissue injury. Herein, we established cadmium (Cd)-exposed rat kidney injury model by intraperitoneal injection with CdCl2 (1.5 mg/kg body weight) and cytotoxicity model of NRK-52E cells by CdCl2 (5 μM) exposure to reveal the role of Nrf2 hyperactivation in Cd-induced nephrotoxicity. Data from the in vitro and in vivo study showed that Cd caused Nrf2 nuclear retention due to nuclear-cytoplasmic depletion of Kelch-like ECH-associated protein 1 (Keap1) and Sequestosome-1(SQSTM1/p62) accumulation, leading to the persistent activation of Nrf2. Moreover, we established inhibited models of Cd-induced prolonged Nrf2 activation using siRNA-mediated gene silencing in vitro and pharmacological inhibition in vivo for subsequent assays. First, Cd-induced cytotoxicity, renal injury and concomitant oxidative stress were markedly alleviated by Nrf2 inhibition. Second, Cd-induced autophagy inhibition was notably alleviated by Nrf2 inhibition. Further, we revealed underlying molecular mechanisms of the crosstalk between persistent activation of Nrf2 and autophagy inhibition in Cd-induced nephrotoxicity. Data showed that Cd-induced lysosomal dysfunction evidenced by impaired lysosomal biogenesis and degradation capacity was markedly recovered by Nrf2 inhibition. Meanwhile, Cd-impaired autophagosome-lysosome fusion was obviously restored by Nrf2 inhibition. In conclusion, our findings revealed that persistent activation of Nrf2 promoted a vicious cycle of oxidative stress and autophagy inhibition in Cd-induced nephrotoxicity.