Nrf2 suppresses lupus nephritis through inhibition of oxidative injury and the NF-κB-mediated inflammatory response

Kidney Int. 2014 Feb;85(2):333-343. doi: 10.1038/ki.2013.343. Epub 2013 Sep 11.

Abstract

The generation of reactive oxygen species has a pivotal role in both acute and chronic glomerular injuries in patients with lupus nephritis. As the transcription factor Nrf2 is a major regulator of the antioxidant response and is a primary cellular defense mechanism, we sought to determine a role of Nrf2 in the progression of lupus nephritis. Pathological analyses of renal biopsies from patients with different types of lupus nephritis showed oxidative damage in the glomeruli, accompanied by an active Nrf2 antioxidant response. A murine lupus nephritis model using Nrf2(+/+) and Nrf2(-/-) mice was established using pristine injection. In this model, Nrf2(-/-) mice suffered from greater renal damage and had more severe pathological alterations in the kidney. In addition, Nrf2(+/+) mice showed ameliorative renal function when treated with sulforaphane, an Nrf2 inducer. Nrf2(-/-) mice had higher expression of transforming growth factor β1 (TGFβ1), fibronectin, and iNOS. In primary mouse mesangial cells, the nephritogenic monoclonal antibody R4A activated the nuclear factor-kappa B (NF-κB) pathway and increased the level of reactive oxygen species, iNOS, TGFβ1, and fibronectin. Knockdown of Nrf2 expression aggravated all aforementioned responses induced by R4A. Thus, these results suggest that Nrf2 improves lupus nephritis by neutralizing reactive oxygen species and by negatively regulating the NF-κB and TGFβ1 signaling pathways.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Case-Control Studies
  • Cells, Cultured
  • DNA Damage
  • Disease Models, Animal
  • Female
  • Fibronectins / metabolism
  • Fullerenes
  • Humans
  • Inflammation Mediators / metabolism*
  • Isothiocyanates / pharmacology
  • Kidney Glomerulus / drug effects
  • Kidney Glomerulus / immunology
  • Kidney Glomerulus / metabolism*
  • Kidney Glomerulus / pathology
  • Lupus Nephritis / chemically induced
  • Lupus Nephritis / genetics
  • Lupus Nephritis / immunology
  • Lupus Nephritis / metabolism
  • Lupus Nephritis / pathology
  • Lupus Nephritis / prevention & control*
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • NF-E2-Related Factor 2 / deficiency
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • NF-kappa B / metabolism*
  • Nitric Oxide Synthase Type II / metabolism
  • Oxidative Stress*
  • RNA Interference
  • Reactive Oxygen Species / metabolism
  • Severity of Illness Index
  • Signal Transduction
  • Transfection
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Antibodies, Monoclonal
  • Fibronectins
  • Fullerenes
  • Inflammation Mediators
  • Isothiocyanates
  • NF-E2-Related Factor 2
  • NF-kappa B
  • NFE2L2 protein, human
  • Nfe2l2 protein, mouse
  • Reactive Oxygen Species
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta1
  • pristine (C60)
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • sulforafan