Cell Stress and Chaperones

, Volume 16, Issue 1, pp 57–68

The Nrf2–Keap1 cellular defense pathway and heat shock protein 70 (Hsp70) response. Role in protection against oxidative stress in early neonatal unilateral ureteral obstruction (UUO)

  • Martin E. Rinaldi Tosi
  • Victoria Bocanegra
  • Walter Manucha
  • Andrea Gil Lorenzo
  • Patricia G. Vallés
Original Paper

DOI: 10.1007/s12192-010-0221-y

Cite this article as:
Rinaldi Tosi, M.E., Bocanegra, V., Manucha, W. et al. Cell Stress and Chaperones (2011) 16: 57. doi:10.1007/s12192-010-0221-y

Abstract

Perturbation of renal tubular antioxidants and overproduction of reactive oxygen species may amplify the proinflammatory state of renal obstruction, culminating in oxidative stress and tubular loss. Here, we analyzed the heat shock protein 70 (Hsp70) response and the function and signal transduction of NF-E2-related protein 2 (Nrf2) transcription factor on oxidative stress modulation in obstruction. Rats were subjected to unilateral ureteral obstruction or sham operation and kidneys harvested at 5, 7, 10, and 14 days after obstruction. Hsp70 expression and Nrf2 activity and its downstream target gene products were assessed. After 10 and 14 days of obstruction, enhanced lipid peroxidation through higher thiobarbituric acid reactive substances levels and increased oxidative stress resulted in reduced total antioxidant activity and enhanced nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase activity were demonstrated. This was accompanied by decreased inducible Hsp70 expression and a progressive reduction of nuclear Nrf2 and its target gene products glutathione S-transferase A2 (GSTA2) and NADPH/quinone oxidoreductase 1 (NQO1), whereas the Nrf2 repressor Kelch-like ECH-associated protein-1 (Keap1) was upregulated. By contrast, on early obstruction for 7 days, lack of increased oxidative markers associated with higher inducible Hsp70 protein levels and a rapid nuclear accumulation of Nrf2, Keap1 downregulation, and mRNA induction of the identified Nrf2-dependent genes, NQO1 and GSTA2, were shown. For these results, we suggest that the magnitude of cytoprotection in early obstruction depends on the combined contribution of induced activation of Nrf2 upregulating its downstream gene products and Hsp70 response. Impaired ability to mount the biological response to the prevailing oxidative stress leading to renal injury was shown in prolonged obstruction.

Keywords

Hsp70/72Nrf2–Keap1Oxidative stressUnilateral ureteral obstruction

Abbreviations

ABTS

2,2′-Azinobis-(3-ethylbenzothiazoline-6-sulfonic acid

AEBSF

4-(2 Aminoethyl)-benzenesulfonyl fluoride

ARE

Antioxidant response elements

CAT

Catalase

CC

Control cortex

CD

Directive Council

CEEA

Ethical Committee of Animal Experimentation of Argentina

CLC

Contralateral cortex

COX-2

Cyclooxygenase-2

GPx

Glutathione peroxidase

GSTA2

Glutathione S-transferase A2

HDAC1

Histone deacetylase 1

HO-1

Heme oxygenase-1

Hsp

Heat shock protein

IL-1

Interleukin-1

IL-6

Interleukin-6

Keap1

Kelch-like ECH-associated protein-1

L-NAME

L-Arginine methyl ester

NADPH

Nicotinamide adenine dinucleotide phosphate reduced

NO

Nitric oxide

NOS

Nitric oxide synthase

NQO1

NADPH/quinone oxidoreductase 1

Nrf2

NF-E2-related nuclear factor erythroid-2

OC

Obstructive cortex

ROS

Reactive oxygen species

SOD

Superoxide dismutase

TAA

Total antioxidant activity

TBARS

Thiobarbituric acid reactive substances

TNF-β

Tumor necrosis factor β

UUO

Unilateral ureteral obstruction

8-OHdG

8-Hydroxy-2′-deoxyguanosine

Copyright information

© Cell Stress Society International 2010

Authors and Affiliations

  • Martin E. Rinaldi Tosi
    • 2
    • 3
  • Victoria Bocanegra
    • 3
  • Walter Manucha
    • 3
  • Andrea Gil Lorenzo
    • 3
  • Patricia G. Vallés
    • 1
    • 2
    • 3
  1. 1.Área de Fisiología Patológica, Departamento de Patología, Facultad de Ciencias MédicasUniversidad Nacional de CuyoMendozaArgentina
  2. 2.Área de Farmacología y Toxicología, Departamento de Farmacia, Facultad de Química, Bioquímica y FarmaciaUniversidad Nacional de San LuisSan LuisArgentina
  3. 3.IMBECU-CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas)MendozaArgentina