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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)

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Cell Stress and Chaperones Aims and scope

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.

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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

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Acknowledgments

This work was performed with financial from CONICET, PICT/2005N°33827 and from the Research and Technology Council of Cuyo University (CIUNC) Mendoza, Argentina/N: 658/05 to P.G. Vallés.

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Authors and Affiliations

  1. Área de Fisiología Patológica, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Centro Universitario, 5500, Mendoza, Argentina

    Patricia G. Vallés

  2. Área de Farmacología y Toxicología, Departamento de Farmacia, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis, Argentina

    Martin E. Rinaldi Tosi & Patricia G. Vallés

  3. IMBECU-CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Mendoza, Argentina

    Martin E. Rinaldi Tosi, Victoria Bocanegra, Walter Manucha, Andrea Gil Lorenzo & Patricia G. Vallés

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  1. Martin E. Rinaldi Tosi
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  2. Victoria Bocanegra
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  3. Walter Manucha
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Correspondence to Patricia G. Vallés.

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Rinaldi Tosi, M.E., Bocanegra, V., Manucha, W. et al. 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). Cell Stress and Chaperones 16, 57–68 (2011). https://doi.org/10.1007/s12192-010-0221-y

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  • DOI: https://doi.org/10.1007/s12192-010-0221-y

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