CONICET | Buscador de Institutos y Recursos Humanos

There is growing evidence that statins may exert renoprotective effects beyond cholesterol reduction. The cholesterol-independent or "pleiotropic" effects of statins include the upregulation of eNOS. The objective of this study was to determine whether eNOS associated with Hsp70 expression is involved in rosuvastatin resistance to obstruction-induced oxidative stress and cell death. Neonatal rats subjected to unilateral ureteral obstruction (UUO) within two days of birth, or sham operation, were treated daily with vehicle or rosuvastatin (10 mg/k/day). Kidneys were harvested 14 days after obstruction. Decreased endogenous NO and lower eNOS expression at mRNA and protein levels associated with downregulation of mRNA Hsf1 and Hsp70 protein expression were shown in the obstructed kidney cortex. Increased NADHP oxidase activity and apoptosis induction; regulated by mitochondrial signal pathway, through the increased pro-apoptotic ratio Bax/BcL2 and caspase 3 activity were demonstrated. Conversely, in cortex membrane fractions from rosuvastatin-treated UUO rats, marked upregulation of eNOS expression at transcriptional and posttranscriptional levels, linked to increased Hsf1 mRNA expression and enhanced Hsp70 at mRNA and protein levels, were observed. Consequently, there was an absence of apoptotic response and transiently decreased NADPH oxidase activity. In addition, interaction between eNOS and Hsp70 was determined by coimmunoprecipitation in cortex membrane fractions, showing overexpression of eNOS associated with increased Hsp70 after rosuvastatin treatment in the obstructed kidney. In conclusion,our data demonstrate that rosuvastatin restore renal NO bioavailability, by eNOS; preventing obstruction-induced oxidative stress and cell death through the induction of heat shock protein 70 (Hsp70) in neonatal UUO

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