Adenine overload induces ferroptosis in human primary proximal tubular epithelial cells.

Autor:	Khan MA; NHMRC CKD CRE (CKD.QLD), University of Queensland, Brisbane, Australia.; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Australia.; Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Brisbane, Australia.; Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, Australia.; Kidney Disease Research Collaborative, Princess Alexandra Hospital and University of Queensland, Translational Research Institute, Brisbane, Australia.; Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj-8100, Dhaka, Bangladesh., Nag P; Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Brisbane, Australia.; Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, Australia., Grivei A; Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Brisbane, Australia.; Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, Australia., Giuliani KTK; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Australia.; Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Brisbane, Australia.; Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, Australia., Wang X; Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Brisbane, Australia.; Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, Australia., Diwan V; NHMRC CKD CRE (CKD.QLD), University of Queensland, Brisbane, Australia.; Centre for Chronic Disease, Faculty of Medicine, University of Queensland, Brisbane, Australia., Hoy W; NHMRC CKD CRE (CKD.QLD), University of Queensland, Brisbane, Australia.; Centre for Chronic Disease, Faculty of Medicine, University of Queensland, Brisbane, Australia., Healy H; NHMRC CKD CRE (CKD.QLD), University of Queensland, Brisbane, Australia.; Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Brisbane, Australia.; Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, Australia.; Centre for Chronic Disease, Faculty of Medicine, University of Queensland, Brisbane, Australia., Gobe G; NHMRC CKD CRE (CKD.QLD), University of Queensland, Brisbane, Australia.; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Australia.; Kidney Disease Research Collaborative, Princess Alexandra Hospital and University of Queensland, Translational Research Institute, Brisbane, Australia.; Centre for Chronic Disease, Faculty of Medicine, University of Queensland, Brisbane, Australia., Kassianos AJ; Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Brisbane, Australia. andrew.kassianos@qimrberghofer.edu.au.; Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, Australia. andrew.kassianos@qimrberghofer.edu.au.; Centre for Chronic Disease, Faculty of Medicine, University of Queensland, Brisbane, Australia. andrew.kassianos@qimrberghofer.edu.au.
Jazyk:	angličtina
Zdroj:	Cell death & disease [Cell Death Dis] 2022 Feb 02; Vol. 13 (2), pp. 104. Date of Electronic Publication: 2022 Feb 02.
DOI:	10.1038/s41419-022-04527-z
Abstrakt:	The pathogenesis of crystal nephropathy involves deposition of intratubular crystals, tubular obstruction and cell death. The deposition of 8-dihydroxyadenine (DHA) crystals within kidney tubules, for instance, is caused by a hereditary deficiency of adenine phosphoribosyl transferase in humans or adenine overload in preclinical models. However, the downstream pathobiological patterns of tubular cell attrition in adenine/DHA-induced nephropathy remain poorly understood. In this study, we investigated: (i) the modes of adenine-induced tubular cell death in an experimental rat model and in human primary proximal tubular epithelial cells (PTEC); and (ii) the therapeutic effect of the flavonoid baicalein as a novel cell death inhibitor. In a rat model of adenine diet-induced crystal nephropathy, significantly elevated levels of tubular iron deposition and lipid peroxidation (4-hydroxynonenal; 4-HNE) were detected. This phenotype is indicative of ferroptosis, a novel form of regulated necrosis. In cultures of human primary PTEC, adenine overload-induced significantly increased mitochondrial superoxide levels, mitochondrial depolarisation, DNA damage and necrotic cell death compared with untreated PTEC. Molecular interrogation of adenine-stimulated PTEC revealed a significant reduction in the lipid repair enzyme glutathione peroxidase 4 (GPX4) and the significant increase in 4-HNE compared with untreated PTEC, supporting the concept of ferroptotic cell death. Moreover, baicalein treatment inhibited ferroptosis in adenine-stimulated PTEC by selectively modulating the mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2) and thus, suppressing mitochondrial superoxide production and DNA damage. These data identify ferroptosis as the primary pattern of PTEC necrosis in adenine-induced nephropathy and establish baicalein as a potential therapeutic tool for the clinical management of ferroptosis-associated crystal nephropathies (e.g., DHA nephropathy, oxalate nephropathy). (© 2022. Crown.)
Databáze:	MEDLINE
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