Kidney Week

Abstract: SA-PO515

NADPH Oxidase (NOX4) and Mitochondrial Injury Contribute to Oxidative Stress and Endothelial Dysfunction in Young Normotensive Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Session Information

• ADPKD: Clinical Studies
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidney

• 1001 Genetic Diseases of the Kidney: Cystic

Authors

• Goksu, Suleyman Yasin, Mayo Clinic, Rochester, Minnesota, United States

Suleyman Yasin Goksu,

• Yilmaz, Gizem, Mayo Clinic, Rochester, Minnesota, United States

Gizem Yilmaz,

• Chebib, Fouad T., Mayo Clinic, Rochester, Minnesota, United States

Fouad T. Chebib,

• Eirin, Alfonso, Mayo Clinic, Rochester, Minnesota, United States

Alfonso Eirin,

• Lerman, Amir, Mayo Clinic, Rochester, Minnesota, United States

Amir Lerman,

• Lerman, Lilach O., Mayo Clinic, Rochester, Minnesota, United States

Lilach O. Lerman,

• Harris, Peter C., Mayo Clinic, Rochester, Minnesota, United States

Peter C. Harris,

• Torres, Vicente E., Mayo Clinic, Rochester, Minnesota, United States

Vicente E. Torres,

• Irazabal, Maria V., Mayo Clinic, Rochester, Minnesota, United States

Maria V. Irazabal,

Background

Endothelial dysfunction (ED) is an independent predictor of cardiovascular (CV) events. In ADPKD, ED and oxidative stress (OS) develop early on, preceding hypertension (HTN) and renal function decline. However, the mechanisms responsible remain unknown. We hypothesized that NOX4 and mitochondrial injury contribute to OS and ED preceding HTN in young normotensive ADPKD patients.

Methods

We prospectively measured plasma levels of homocysteine (Hcy), 8-isoprostane, NOX4 and the mtDNA genes cytochrome-c oxidase-3 (COX3) and nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit-1 (ND1), in young, normotensive (without BP medication) ADPKD patients, and age/gender-matched healthy volunteers (HV) (n=10, each). Total kidney volume (TKV) and Renal Blood Flow (RBF) were evaluated by MRI.

Results

BP levels were higher in ADPKD, and HtTKV was twofold higher in ADPKD vs. controls. Yet, eGFR and RBF were similar between the groups (Table). Plasma Hcy, 8-isoprostanes and NOX4 were higher in ADPKD (Figure), and correlated directly with HtTKV (p<0.05, figure), but the correlation with RBF was not significant. Plasma mtDNA levels were lower in ADPKD vs controls, and correlated inversely with HtTKV (R² 0.397 and 0.392 respectively).

Conclusion

Early ADPKD is associated with elevated Hcy, 8-isoprostane, and NOX4, and decreased mtDNA levels, which precede the reduction in RBF and the development of HTN, and are associated with disease severity. These findings suggest that NOX4 and mitochondrial abnormalities contribute to oxidative stress, endothelial dysfunction, and possibly the development of HTN and disease progression in ADPKD

Funding

• Private Foundation Support