title: Role of mitochondria in paricalcitol-mediated cytoprotection during obstructive nephropathy.
abstract: Vitamin D slows the progression of chronic kidney disease. Furthermore, activators of vitamin D receptors (VDR) have 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 an obstructive nephropathy model [unilateral ureteral obstruction (UUO)]. 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 (30 ng/kg). The following were determined: biochemical parameters; fibrosis; apoptosis; mitochondrial morphology; VDR, AT(1) 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 AT(1)-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). These results suggest that paricalcitol confers a protective effect and reveal, as well, a possible AT(1) receptor-dependent protective effect that occurs at the mitochondrial level.
authors.affiliation: Área de Fisiopatología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina.
authors.forename: Isabel Mercedes
authors.initials: IM
authors.lastname: García
authors.forename: Liliana
authors.initials: L
authors.lastname: Altamirano
authors.forename: Luciana
authors.initials: L
authors.lastname: Mazzei
authors.forename: Miguel
authors.initials: M
authors.lastname: Fornés
authors.forename: Marisa Nile
authors.initials: MN
authors.lastname: Molina
authors.forename: León
authors.initials: L
authors.lastname: Ferder
authors.forename: Walter
authors.initials: W
authors.lastname: Manucha
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects*; D004872:Ergocalciferols / Q000494:pharmacology* / Q000627:therapeutic use; D005355:Fibrosis; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D011921:Rats, Inbred WKY; D012084:Renin-Angiotensin System; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology*
chemical_list: D004872:Ergocalciferols; C084656:paricalcitol