Mitochondrial dysfunction and oxidative stress in patients with chronic kidney disease

作     者：Gamboa, Jorge L. Billings, Frederic T. Bojanowski, Matthew T. Gilliam, Laura A. Yu, Chang Roshanravan, Baback Roberts, L. Jackson, II Himmelfarb, Jonathan Ikizler, T. Alp Brown, Nancy J. 

作者机构：Vanderbilt Univ Med Ctr Div Clin Pharmacol Nashville TN USA Vanderbilt Univ Med Ctr Dept Anesthesiol Nashville TN USA East Carolina Univ Dept Physiol Greenville NC USA Vanderbilt Univ Med Ctr Dept Biostat Nashville TN USA Univ Washington Kidney Res Inst Seattle WA 98195 USA Vanderbilt Univ Med Ctr Dept Med Div Nephrol Nashville TN USA 

出 版 物：《PHYSIOLOGICAL REPORTS》 (Physiol. Rep.)

年 卷 期：2016年第4卷第9期

页      面：12780-12780页

基　　金：NCRR NIH HHS [UL1 RR024975, 1UL-1RR024975] Funding Source: Medline NHLBI NIH HHS [R01 HL065193, 5R01HL065193] Funding Source: Medline NIAMS NIH HHS [F32AR061946, F32 AR061946] Funding Source: Medline NIDDK NIH HHS [K23 DK099442, K23 DK100533, K24DK062849, K23DK100533, K24 DK062849, DK020593] Funding Source: Medline NIGMS NIH HHS [R01 GM112871, K23 GM102676, K23GM102676, T32GM07569, R01GM112871] Funding Source: Medline 

主　　题：BNIP3 chronic kidney disease mitochondria mitochondrial DNA copy number oxidative stress PGC1 alpha skeletal muscle 

摘      要：Mitochondria abnormalities in skeletal muscle may contribute to frailty and sarcopenia, commonly present in patients with chronic kidney disease (CKD). Dysfunctional mitochondria are also a major source of oxidative stress and may contribute to cardiovascular disease in CKD. We tested the hypothesis that mitochondrial structure and function worsens with the severity of CKD. Mitochondrial volume density, mitochondrial DNA (mtDNA) copy number, BNIP3, and PGC1 alpha protein expression were evaluated in skeletal muscle biopsies obtained from 27 subjects (17 controls and 10 with CKD stage 5 on hemodialysis). We also measured mtDNA copy number in peripheral blood mononuclear cells (PBMCs), plasma isofurans, and plasma F2-isoprostanes in 208 subjects divided into three groups: non-CKD (eGFR60 mL/min), CKD stage 3-4 (eGFR 60-15 mL/min), and CKD stage 5 (on hemodialysis). Muscle biopsies from patients with CKD stage 5 revealed lower mitochondrial volume density, lower mtDNA copy number, and higher BNIP3 content than controls. mtDNA copy number in PBMCs was decreased with increasing severity of CKD: non-CKD (6.48, 95% CI 4.49-8.46), CKD stage 3-4 (3.30, 95% CI 0.85-5.75, P = 0.048 vs. non-CKD), and CKD stage 5 (1.93, 95% CI 0.27-3.59, P = 0.001 vs. non-CKD). Isofurans were higher in patients with CKD stage 5 (median 59.21 pg/mL, IQR 41.76-95.36) compared to patients with non-CKD (median 49.95 pg/mL, IQR 27.88-83.46, P = 0.001), whereas F2-isoprostanes did not differ among groups. Severity of CKD is associated with mitochondrial dysfunction and markers of oxidative stress. Mitochondrial abnormalities, which are common in skeletal muscle from patients with CKD stage 5, may explain the muscle dysfunction associated with frailty and sarcopenia in CKD. Further studies are required to evaluate mitochondrial function in vivo in patients with different CKD stages.