Aouichat, SamiraNavarro-Alarcon, MiguelAlarcón-Guijo, PabloSalagre, DiegoNcir, MarwaZourgui, LazharAgil, Ahmad2022-10-312022-10-312021-03-08Aouichat S, Navarro-Alarcon M, Alarcón-Guijo P, Salagre D, Ncir M, Zourgui L, et al. Melatonin Improves Endoplasmic Reticulum Stress-Mediated IRE1α Pathway in Zücker Diabetic Fatty Rat. Pharmaceuticals. 2021 Mar 8;14(3):232http://hdl.handle.net/10668/4305Obesity and diabetes are linked to an increased prevalence of kidney disease. Endoplasmic reticulum stress has recently gained growing importance in the pathogenesis of obesity and diabetes-related kidney disease. Melatonin, is an important anti-obesogenic natural bioactive compound. Previously, our research group showed that the renoprotective effect of melatonin administration was associated with restoring mitochondrial fission/fusion balance and function in a rat model of diabesity-induced kidney injury. This study was carried out to further investigate whether melatonin could suppress renal endoplasmic reticulum (ER) stress response and the downstream unfolded protein response activation under obese and diabetic conditions. Zücker diabetic fatty (ZDF) rats and lean littermates (ZL) were orally supplemented either with melatonin (10 mg/kg body weight (BW)/day) (M-ZDF and M-ZL) or vehicle (C-ZDF and C-ZL) for 17 weeks. Western blot analysis of ER stress-related markers and renal morphology were assessed. Compared to C-ZL rats, higher ER stress response associated with impaired renal morphology was observed in C-ZDF rats. Melatonin supplementation alleviated renal ER stress response in ZDF rats, by decreasing glucose-regulated protein 78 (GRP78), phosphoinositol-requiring enzyme1α (IRE1α), and ATF6 levels but had no effect on phospho-protein kinase RNA-like endoplasmic reticulum kinase (PERK) level. In addition, melatonin supplementation also restrained the ER stress-mediated apoptotic pathway, as indicated by decreased pro-apoptotic proteins phospho-c-jun amino terminal kinase (JNK), Bax, and cleaved caspase-3, as well as by upregulation of B cell lymphoma (Bcl)-2 protein. These improvements were associated with renal structural recovery. Taken together, our findings revealed that melatonin play a renoprotective role, at least in part, by suppressing ER stress and related pro-apoptotic IRE1α/JNK signaling pathway.enAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/MelatoninEndoplasmic reticulum stressDiabesityKidneyCaspase-3B cell lymphomaObesityJNK Mitogen-Activated Protein KinasesMelatoninaEstrés del retículo endoplásmicoRiñónCaspasa 3Linfoma de células BObesidadProteínas quinasas JNK activadas por mitógenosMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::RatsMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 2-Ring::Indoles::Tryptamines::MelatoninMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Peptide Hydrolases::Cysteine Proteases::Cysteine Endopeptidases::Caspases::Caspases, Effector::Caspase 3Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intracellular Signaling Peptides and Proteins::Apoptosis Regulatory Proteins::Proto-Oncogene Proteins c-bcl-2::bcl-2-Associated X ProteinMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Endoplasmic Reticulum StressMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Signal Transduction::MAP Kinase Signaling SystemMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Mitochondrial Turnover::Mitochondrial DynamicsMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Vital Statistics::Morbidity::PrevalenceMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Up-RegulationMedical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::ObesityMedical Subject Headings::Diseases::Endocrine System Diseases::Diabetes MellitusMedical Subject Headings::Technology and Food and Beverages::Food and Beverages::Food::Dietary SupplementsMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Molecular Probe Techniques::Blotting, WesternMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Serine-Threonine Kinases::Mitogen-Activated Protein Kinases::JNK Mitogen-Activated Protein KinasesMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Peptide Biosynthesis::Protein Biosynthesis::Protein Modification, Translational::Protein Processing, Post-Translational::Unfolded Protein ResponseMedical Subject Headings::Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::Endoplasmic ReticulumMedical Subject Headings::Diseases::Neoplasms::Neoplasms by Histologic Type::Lymphoma::Lymphoma, Non-Hodgkin::Lymphoma, B-CellMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein KinasesMedical Subject Headings::Diseases::Male Urogenital Diseases::Urologic Diseases::Kidney DiseasesMedical Subject Headings::Anatomy::Urogenital System::Urinary Tract::KidneyMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Serine-Threonine Kinasesresearch article33800157open access10.3390/ph140302321424-8247PMC8001258