Role of mitochondria-derived reactive oxygen species in microvascular dysfunction in chronic kidney disease

Cardiovascular disease is the leading cause of mortality in chronic kidney disease (CKD). Mitochondrial dysfunction secondary to CKD is a potential source of oxidative stress that may impair vascular function. This study sought to determine if mitochondria-derived reactive oxygen species contribute to microvascular dysfunction in stage 3-5 CKD. Cutaneous vasodilation in response to local heating was assessed in 20 CKD patients [60 +/- 13 yr; estimated glomerular filtration rate (eGFR) 46 +/- 13 ml.kg(-1).1.73 m(-2)] and 11 matched healthy participants (58 +/- 2 yr; eGFR >90 ml.kg(-1).1.73 m(-2)). Participants were instrumented with two microdialysis fibers for the delivery of 1) Ringer solution, and 2) the mitochondria-specific superoxide scavenger MitoTempo. Skin blood flow was measured via laser Doppler flowmetry during standardized local heating (42 degrees C). Cutaneous vascular conductance (CVC) was calculated as a percentage of the maximum conductance achieved with sodium nitroprusside infusion at 43 degrees C. Urinary isofuran/F-2-isoprostane ratios were assessed by gas-chromatography mass spectroscopy. Isofuran-to-F-2-isoprostane ratios were increased in CKD patients (3.08 +/- 0.32 vs. 1.69 +/- 0.12 arbitrary units; P < 0.01) indicative of mitochondria-derived oxidative stress. Cutaneous vasodilation was impaired in CKD compared with healthy controls (87 +/- 1 vs. 92 +/- 1% CVCmax; P < 0.01). Infusion of MitoTempo significantly increased the plateau phase CVC in CKD patients (CKD Ringer vs. CKD MitoTempo: 87 +/- 1 vs. 93 +/- 1% CVCmax; P < 0.01) to similar levels observed in healthy controls (P = 0.9). These data provide in vivo evidence that mitochondria-derived reactive oxygen species contribute to microvascular dysfunction in CKD and suggest that mitochondrial dysfunction may be a potential therapeutic target to improve CKD-related vascular dysfunction.