CONICET | Buscador de Institutos y Recursos Humanos

Intrarenal renin-angiotensin system (RAS) activity is increased during early development and is further enhanced by unilateral ureteral obstruction (UUO). We studied the involvement of mitogen-activated protein (MAP) kinase members, and the RhoA GTPase signaling pathways on the regulation of renal cell response after AT1 Angiotensin II receptor inhibition in obstruction Neonatal rats subjected to sham operation or complete UUO within the first 48 hours of life received saline vehicle, Losartan (AT1 inhibitor), or PD-123319 (AT2 inhibitor) during the first 14 days of life. Cortex tubular epithelial cell apoptotic response was shown by TUNEL and confirmed by electron microscopy associated with mitochondrial signaling pathway through the increased proapoptotic ratio Bax/BcL-2 and, consequently increased caspase 3 expression and activity in obstructed kidney before and after Type 1 (AT1) receptor blockade. Non injury of contralatertal kidney was shown. The convergence of two independent signal pathways the RhoA GTPase and pERK and concurrent inhibition of JNK MAP kinase were required for the apoptotic response in 14 day kidney obstructed tubular cells either with and without losartan treatment Absence of increased AT2 protein expression after AT1 receptor inhibition on day 14 of obstruction was shown. Selective angiotensinAT2-receptor inhibition with PD-123319 had no protective effect on the renal response to complete 14 day UUO. We suggest a role of both , Rho A GTPase activation and the opposing actions of the ERK and JNK-p38 MAP kinase signaling pathways as events involved in tubular cell apoptosis regulation after AT1 receptor inhibition in neonatal UUO.