title: Probucol ameliorates renal and metabolic sequelae of primary CoQ deficiency in Pdss2 mutant mice.
abstract: Therapy of mitochondrial respiratory chain diseases is complicated by limited understanding of cellular mechanisms that cause the widely variable clinical findings. Here, we show that focal segmental glomerulopathy-like kidney disease in Pdss2 mutant animals with primary coenzyme Q (CoQ) deficiency is significantly ameliorated by oral treatment with probucol (1% w/w). Preventative effects in missense mutant mice are similar whether fed probucol from weaning or for 3 weeks prior to typical nephritis onset. Furthermore, treating symptomatic animals for 2 weeks with probucol significantly reduces albuminuria. Probucol has a more pronounced health benefit than high-dose CoQ(10) supplementation and uniquely restores CoQ(9) content in mutant kidney. Probucol substantially mitigates transcriptional alterations across many intermediary metabolic domains, including peroxisome proliferator-activated receptor (PPAR) pathway signaling. Probucol's beneficial effects on the renal and metabolic manifestations of Pdss2 disease occur despite modest induction of oxidant stress and appear independent of its hypolipidemic effects. Rather, decreased CoQ(9) content and altered PPAR pathway signaling appear, respectively, to orchestrate the glomerular and global metabolic consequences of primary CoQ deficiency, which are both preventable and treatable with oral probucol therapy.
authors.affiliation: Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. falkm@email.chop.edu
authors.forename: Marni J
authors.initials: MJ
authors.lastname: Falk
authors.forename: Erzsebet
authors.initials: E
authors.lastname: Polyak
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Peng
authors.forename: Rhonda
authors.initials: R
authors.lastname: King
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Maltzman
authors.forename: Ezinne
authors.initials: E
authors.lastname: Okwuego
authors.forename: Oksana
authors.initials: O
authors.lastname: Horyn
authors.forename: Eiko
authors.initials: E
authors.lastname: Nakamaru-Ogiso
authors.forename: Julian
authors.initials: J
authors.lastname: Ostrovsky
authors.forename: Letian X
authors.initials: LX
authors.lastname: Xie
authors.forename: Jia Yan
authors.initials: JY
authors.lastname: Chen
authors.forename: Beth
authors.initials: B
authors.lastname: Marbois
authors.forename: Itzhak
authors.initials: I
authors.lastname: Nissim
authors.forename: Catherine F
authors.initials: CF
authors.lastname: Clarke
authors.forename: David L
authors.initials: DL
authors.lastname: Gasser
mesh_terms: D000419:Albuminuria / Q000188:drug therapy; D019883:Alkyl and Aryl Transferases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D006943:Hyperglycemia / Q000188:drug therapy; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D018384:Oxidative Stress; D011341:Probucol / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology; D014451:Ubiquinone / Q000172:deficiency*
chemical_list: D000924:Anticholesteremic Agents; D000975:Antioxidants; D014451:Ubiquinone; D019883:Alkyl and Aryl Transferases; D011341:Probucol