title: Cadmium-induced autophagy in rat kidney: an early biomarker of subtoxic exposure.
abstract: Environmental exposures to cadmium (Cd) are a major cause of human toxicity. The kidney is the most sensitive organ; however, the natures of injuries and of adaptive responses have not been adequately investigated, particularly in response to environmental relevant Cd concentrations. In this study, rats received a daily ip injection of low CdCl₂ dose (0.3 mg Cd/kg body mass) and killed at 1, 3, and 5 days of intoxication. Functional, ultrastructural, and biochemical observations were used to evaluate Cd effects. We show that Cd at such subtoxic doses does not affect the tubular functions nor does it induce apoptosis. Meanwhile, Cd accumulates within lysosomes of proximal convoluted tubule (PCT) cells where it triggers cell proliferation and autophagy. By developing an immunohistochemical assay, a punctate staining of light chain 3-II is prominent in Cd-intoxicated kidneys, as compared with control. We provide the evidence of a direct upregulation of autophagy by Cd using a PCT cell line. Compared with the other heavy metals, Cd is the most powerful inducer of endoplasmic reticulum stress and autophagy in PCT cells, in relation to the hypersensitivity of PCT cells. Altogether, these findings suggest that kidney cortex adapts to subtoxic Cd dose by activating autophagy, a housekeeping process that ensures the degradation of damaged proteins. Given that Cd is persistent within cytosol, it might damage proteins continuously and impair at long-term autophagy efficiency. We therefore propose the autophagy pathway as a new sensitive biomarker for renal injury even after exposure to subtoxic Cd doses.
authors.affiliation: Faculté de Médecine de Tunis, Unité de Recherches n° 01/UR/08-07, 15 Rue Djebel Lakhdhar, La Rabta, 1007 Tunis, Tunisie.
authors.forename: Abderrahman
authors.initials: A
authors.lastname: Chargui
authors.forename: Sami
authors.initials: S
authors.lastname: Zekri
authors.forename: Gregory
authors.initials: G
authors.lastname: Jacquillet
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rubera
authors.forename: Marius
authors.initials: M
authors.lastname: Ilie
authors.forename: Amine
authors.initials: A
authors.lastname: Belaid
authors.forename: Christophe
authors.initials: C
authors.lastname: Duranton
authors.forename: Michel
authors.initials: M
authors.lastname: Tauc
authors.forename: Paul
authors.initials: P
authors.lastname: Hofman
authors.forename: Philippe
authors.initials: P
authors.lastname: Poujeol
authors.forename: Michèle V
authors.initials: MV
authors.lastname: El May
authors.forename: Baharia
authors.initials: B
authors.lastname: Mograbi
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D002104:Cadmium / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D015415:Biomarkers; D002104:Cadmium