Mitochondria-Targeted Antioxidant Therapy Ameliorates Arterial Dysfunction in a Mouse Model of Autosomal Dominant Polycystic Kidney Disease

Background: Cardiovascular diseases (CVD) are the leading cause of death in adults with ADPKD in part due to arterial dysfunction, e.g. endothelial dysfunction and aortic stiffening. ADPKD-associated arterial dysfunction appears to be mediated by impaired nitric oxide (NO) bioavailability secondary to excess mitochondria-derived reactive oxygen species. We tested efficacy of oral supplementation with mitochondrial antioxidant MitoQ (MQ) for improving arterial function in an orthologous mouse model of ADPKD. Methods: Male/female C57Bl/6J Pkd1RC/RC mice were supplemented with 250 µM MQ in drinking water from 4-10 mo of age (i.e. mild to severe kidney disease) vs control water (n=5-8/group/sex). At intervention end, we assessed in vivo aortic stiffness as aortic pulse wave velocity (PWV) and endothelial function as endothelium-dependent dilation (EDD) to acetylcholine in isolated carotid arteries. Aorta rings were collected to assess aortic elastic modulus (EM), a measure of stiffness that isolates structural factors, and for histology. Key assessments were also made in wildtype (WT) mice (n=9/sex). Data are mean±SD. Stats are 1-way ANOVA with Tukey’s post-hoc. Results: Control Pkd1RC/RC (CONT) mice had impaired carotid artery EDD (peak EDD: 79±11 vs WT: 95±3 %, P<0.001) that was ameliorated by MQ (91±6%, P<0.01) via enhanced NO bioavailability (Δpeak EDD ± the NO synthase inhibitor L-NAME, CONT: 32±21 vs MQ: 48±10 %, P=0.03). There were no sex differences for endothelial function. Aortic PWV was higher in CONT Pkd1RC/RC vs WT mice (males: 447±36 vs 346±29 cm/s; females: 426±17 vs 369±26 cm/s; both P<0.01). MQ attenuated in vivo aortic stiffening in male (400±15 cm/s, P=0.02) but not female (427±39 cm/s, P>0.99) mice, and also lowered aortic ex vivo stiffness in male mice only (EM, CONT: 6437±1477 vs MQ: 4691±1790, P=0.08). However, aortic medial collagen content (Masson-trichrome, CONT: 25±12 vs MQ: 17±12%; P=0.05) was lower with MQ in both sexes, suggesting reduced fibrosis. Conclusion: MQ supplementation in an orthologous model of ADPKD improves conduit artery endothelial function and arterial stiffness, although there may be some sex differences in efficacy. MQ represents a promising strategy for treating arterial dysfunction, and thereby reducing CVD risk, in ADPKD.