Kidney Week

Abstract: FR-PO607

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

Session Information

• Cystic Kidney Diseases: Mechanisms and Models
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Dwivedi, Nidhi, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Nidhi Dwivedi, PhD

• Stone, Brittany A., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Brittany A. Stone, MS

• Clayton, Zachary S., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Zachary S. Clayton

• Chonchol, Michel, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Michel Chonchol, MD, FASN

• Gitomer, Berenice Y., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Berenice Y. Gitomer, PhD

• Hopp, Katharina, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Katharina Hopp, PhD

• Brunt, Vienna E., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Vienna E. Brunt, PhD

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 Pkd1^RC/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 Pkd1^RC/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 Pkd1^RC/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.