Mitochondrial cytoprotective effects paricalcitol-mediated during obstructive nephropathy

ISABEL MERCEDES GARCíA; LILIANA ALTAMIRANO; LUCIANA MAZZEI; WALTER MANUCHA

Potrero de los Funes, San Luis

Jornada; XXX Reunión Anual de la Sociedad de Biología de Cuyo; 2012

Sociedad de Biología de Cuyo

Recently, activators of vitamin D receptors (VDR) have demonstrated suppressant effects on the renin-angiotensin system, as well as anti-inflammatory and antifibrotic actions. This study aimed to evaluate the cytoprotective effects of paricalcitol, a VDR activator, at the mitochondrial level using the unilateral ureteral obstruction (UUO) model. Rats subjected to UUO and controls were treated daily with vehicle or paricalcitol. The control group underwent a sham surgery. The treatment was done for 15 days (30ng/kg). The following were determined: biochemical parameters, fibrosis/ apoptosis, mitochondrial morphology, VDR, AT1 receptor, and NADPH oxidase 4 expression, and NADPH oxidase activity (in total and in mitochondrial fractions from the renal cortex). VDR activation prevented fibrosis (20±5 vs. 60±10%) and the number of TUNEL-positive apoptotic cells (10±3 vs. 25±4) in UUO. Biochemical, histological, and molecular studies suggest mitochondrial injury. Electron microscopy revealed in UUO electronically luminous material in the nucleus. Some mitochondria were increased in size and contained dilated crests and larger than normal spaces in their interiors. These changes were not present with paricalcitol treatment. Additionally, high AT1-receptor mRNA and NADPH activity was reverted in mitochondrial fractions from obstructed paricalcitol-treated animals (0.58±0.06 vs. 0.95±0.05 relative densitometry units and 9,000±800 vs. 15,000±1,000 relative fluorescence units·μg protein (-1)·min(-1), respectively). These changes were consistent with an improvement in VDR expression (0.75±0.05 vs. 0.35±0.04 relative densitometry units). In conclusion, presents results suggest that VDR induction confers a protective effect and reveal, as well, a possible AT1 receptor-dependent protective effect that occurs at the mitochondrial level.