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Probucol ameliorates renal and metabolic sequelae of primary CoQ deficiency in Pdss2 mutant mice

, : Probucol ameliorates renal and metabolic sequelae of primary CoQ deficiency in Pdss2 mutant mice. Embo Molecular Medicine 3(7): 410-427

Therapy of mitochondrial respiratory chain diseases is complicated by limited understanding of cellular mechanisms, which cause the widely variable clinical findings. Here, we show that focal segmental glomerulopathy-like kidney disease in Pdss2 mutant animals with primary coenzyme Q deficiency is significantly ameliorated by oral treatment with probucol (1% wt/wt). Preventative effects in missense mutant mice are similar whether fed probucol from weaning or for three weeks prior to typical nephritis onset. Furthermore, treating symptomatic animals for two weeks with probucol significantly reduces albuminuria. Probucol has a more pronounced health benefit than high-dose CoQ1 supplementation and uniquely restores CoQ9 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 CoQ9 content and altered PPAR pathway signaling appear to respectively orchestrate the glomerular and global metabolic consequences of primary coenzyme Q deficiency, which are both preventable and treatable with oral probucol therapy.


PMID: 21567994

DOI: 10.1002/emmm.201100149

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