Endoplasmic reticulum stress response and inflammatory cytokines in type 2 diabetic nephropathy: Role of indoleamine 2,3-dioxygenase and programmed death-1

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32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)343-351
Number of pages9
JournalExperimental and Molecular Pathology
Volume94
Issue number2
DOIs
StatePublished - Apr 1 2013

Keywords

  • Cell death
  • Cytokines
  • Diabetes
  • ER stress response
  • Indoleamine 2,3-dioxygenase
  • Kidney
  • Programmed death-1

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Clinical Biochemistry

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