title: Endoplasmic reticulum stress response and inflammatory cytokines in type 2 diabetic nephropathy: role of indoleamine 2,3-dioxygenase and programmed death-1.
abstract: We tested the hypotheses that a) type 2 diabetes increases endoplasmic reticulum (ER) stress response, production of pro-inflammatory cytokines and kidney cell death and b) downregulations of renal indoleamine 2,3-dioxygenase (IDO) and programmed death-1 (PD-1) contribute to exacerbated inflammation and tissue injury. The growth arrest and DNA damage-inducible protein 153 (GADD153; a marker of ER stress response), inflammatory cytokines and cell death were determined in the context of assessment of IDO and PD-1 in an animal model of type 2 diabetic nephropathy (i.e., db/db mouse). Peripheral blood of 4-month-old db/db mice manifested significantly greater percents of interleukin (IL)-17 and IL-23 positive cells in association with greater percents of cells that were positive for PD-1 or GADD153. Compared to kidneys of db/m controls, renal cells prepared from kidneys of db/db mice displayed a) increased percent of cells that were positive for IL-17, IL-23, PD-1 and GADD153, b) decreased JC-1 aggregates but increased JC-1 monomers suggestive of disruption of mitochondrial membrane potential and c) increased apoptotic and necrotic cell death. Immunohistochemical analyses also revealed increased staining of renal tissue of db/db mice for IL-17, IL23, GADD153, Annexin V, caspase 3, PD-1 and IDO compared to db/m kidneys; these changes were generally more prominent in the glomeruli. In conclusion, type 2 diabetes upregulates systemic and local ER stress response and pro-inflammatory mechanisms thereby contributing to renal injury. However, the accompanying upregulations of PD-1 and IDO likely reflect activation of compensatory mechanisms to curtail inflammation and cell injury.
authors.affiliation: Department of Oral Biology, College of Dental Medicine, Georgia Health Sciences University, Augusta, GA 30912, United States. Bbaban@georgiahealth.edu
authors.forename: Babak
authors.initials: B
authors.lastname: Baban
authors.forename: Jun Yao
authors.initials: JY
authors.lastname: Liu
authors.forename: Mahmood S
authors.initials: MS
authors.lastname: Mozaffari
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism*; D015536:Down-Regulation; D059865:Endoplasmic Reticulum Stress; D005786:Gene Expression Regulation; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000032:analysis
chemical_list: D017304:Annexin A5; C497249:DDIT3 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D020381:Interleukin-17; D053759:Interleukin-23; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D051742:Transcription Factor CHOP; D053148:Caspase 3