INVESTIGADORES
MANUCHA Walter Ariel Fernando
artículos
Título:
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)
Autor/es:
MARTÍN E RINALDI TOSI; VICTORIA BOCANEGRA; WALTER MANUCHA; ANDREA GIL LORENZO; PATRICIA G. VALLES
Revista:
CELL STRESS & CHAPERONES.
Editorial:
SPRINGER
Referencias:
Lugar: Netherlands; Año: 2011 vol. 16 p. 57 - 68
ISSN:
1355-8145
Resumen:
Perturbation of renal tubular antioxidants and overproduction of ROS may amplify the
proinflammatory state of renal obstruction, culminating in oxidative stress and tubular
loss. Here, we analyzed the 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 UUO 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 TBARS levels and increased oxidative
stress, resulted in reduced total antioxidant activity and enhanced 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
Glutathion 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.