CYTOPROTECTIVE ROLE OF NITRIC OXIDE ASSOCIATED WITH Hsp70 EXPRESSION IN NEONATAL OBSTRUCTIVE NEPHROPATHY

WALTER MANUCHA; PATRICIA G. VALLES

NITRIC OXIDE-BIOLOGY AND CHEMISTRY

Orlando Fl Academic Press

Lugar: Orlando ; Año: 2008 vol. 18 p. 204 - 215

1089-8603

Nitric oxide (NO) has emerged as an important endogenous inhibitor of apoptosis. In this study, we postulated that the mechanism of apoptosis inhibition by NO would include stimulation of Hsp70 expression. Rats were subjected to unilateral ureteral obstruction (UUO) or sham operation, and kidneys were harvested 5 and 14 days after obstruction. After 14 days of obstruction, decreased endogenous NO and lower iNOS expression at mRNA and protein levels associated with downregulation of Hsp70 protein expression were shown in apoptosis induction, regulated by mitochondrial signal pathway, through the increased pro-apoptotic ratio Bax/BcL2 and consequently caspase 3 activity. Conversely, 5 days after kidney obstruction, increased Hsp70 expression linked to increased NO and iNOS expression at transcriptional and posttranscriptional levels with absence of apoptotic response, were demonstrated. In vitro pretreatment of cortex homogenates with a NO donor sodium nitroprusside (SNP) induced the expression of heat shock protein 70 (Hsp70), which was associated with cytoprotection from apoptosis and transiently decreased NADPH oxidase activity associated with increased superoxide dismutase activity. Opposite effects were obtained after L-NAME pretreatment. Interaction between BcL2 and Hsp70 in the presence of an NO donor (SNP) and inhibitor (L-NAME), was determined by coimmunoprecipitation. Binding of BcL2 and Hsp70 increased after exposure to NO donor (SNP). These findings suggest that NO can produce resistance to obstruction-induced cell death by mitochondrial apoptotic pathway, through the induction of heat shock protein 70 expression in neonatal unilateral ureteral obstruction.