ROLE OF MITOCHONDRIA IN PARICALCITOL-MEDIATED CYTOPROTECTION DURING OBSTRUCTIVE NEPHROPATHY

ISABEL MERCEDES GARCÍA; LUCIANA MAZZEI; LILIANA ALTAMIRANO; MIGUEL FORNÉS; LEÓN FERDER; WALTER MANUCHA

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY - (Print)

Bethesda, Md. : American Physiological Society

Año: 2012 vol. 302 p. 1595 - 1605

0363-6127

Background: Vitamin D slows the progression of chronic kidney disease. Further, activators of vitamin D receptors (VDR) have suppressant effects on the renin-angiotensin system (RAS) as well as anti-inflammatory and anti-fibrotic actions. Aim: This study aimed to evaluate the cytoprotective effects of paricalcitol, a VDR activator, at the mitochondrial level using an obstructive nephropathy model (unilateral ureteral obstruction [UUO]). Methods: 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 NOX4 expression; and NADPH oxidase activity (in total and in mitochondrial fractions from the renal cortex). Results: VDR activation prevented fibrosis (20 ± 5 vs. 60 ± 10) and apoptosis (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 and 9000 ± 800 vs.15000 ± 1000, respectively). These changes were consistent with an improvement in VDR expression (0.75 ± 0.05 vs. 0.35 ± 0.04) Conclusions: These results suggest that paricalcitol confers a protective effect and reveal, as well, a possible AT1 receptor-dependent protective effect that occurs at the mitochondrial level.