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Published on: January 22, 2017
Probucol ameliorates renal and metabolic sequelae of primary CoQ deficiency in Pdss2 mutant mice
Marni J Falk1, Erzsebet Polyak, Zhe Zhang
1Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. falkm@email.chop.edu
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.
Insights
Oral probucol therapy effectively treats primary coenzyme Q (CoQ) deficiency in mice with kidney disease. Probucol ameliorates kidney damage and metabolic dysfunction, outperforming CoQ(10) supplementation.
Area of Science:
- Biochemistry
- Genetics
- Nephrology
Background:
- Mitochondrial respiratory chain diseases present variable clinical findings due to poorly understood cellular mechanisms.
- Primary coenzyme Q (CoQ) deficiency, caused by Pdss2 mutations, leads to focal segmental glomerulopathy-like kidney disease in affected animals.
Purpose of the Study:
- To investigate the therapeutic potential of oral probucol in ameliorating kidney disease and metabolic dysfunction associated with primary CoQ deficiency.
- To compare the efficacy of probucol with CoQ(10) supplementation and elucidate probucol's mechanism of action.
Main Methods:
- Administration of oral probucol to Pdss2 mutant mice at different stages of the disease (preventative and therapeutic).
- Assessment of kidney pathology, albuminuria, CoQ content, and transcriptional alterations, including PPAR pathway signaling.
- Comparison of probucol's effects with high-dose CoQ(10) supplementation.
Main Results:
- Oral probucol significantly ameliorated kidney disease and reduced albuminuria in Pdss2 mutant mice.
- Probucol treatment restored CoQ(9) content in mutant kidneys and mitigated widespread transcriptional alterations, notably within the PPAR pathway.
- Probucol demonstrated a more pronounced health benefit than high-dose CoQ(10) supplementation, independent of its hypolipidemic effects.
Conclusions:
- Primary CoQ deficiency leads to glomerular and global metabolic consequences orchestrated by decreased CoQ(9) and altered PPAR signaling.
- Oral probucol therapy is a promising preventative and therapeutic strategy for the renal and metabolic manifestations of primary CoQ deficiency.
- Probucol's beneficial effects highlight its potential as a treatment for mitochondrial respiratory chain diseases characterized by CoQ deficiency.
