title: Markers of inflammation, proteolysis, and apoptosis in ESRD.
abstract: BACKGROUND
  Hemodialysis (HD) is associated with protein catabolism and augmented apoptosis. Although the effect of metabolic acidosis and inflammatory cytokines on activation of the ubiquitin-proteasome pathway and branched-chain keto acid dehydrogenase (BCKAD) is well known, the effect of HD on these pathways remains unexplored.
  
  
  METHODS
  Twelve patients with end-stage renal disease were studied before and during HD. Eight controls also were studied. Plasma levels of complement components and cytokines, interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-alpha) were measured. Messenger RNA (mRNA) levels of caspase-3, a mediator of apoptosis; ubiquitin, a marker of proteolysis; and BCKAD-E2, an enzyme regulating branched-chain amino acid oxidation, were estimated in skeletal muscle biopsy specimens by means of reverse-transcriptase polymerase chain reaction. Annexin-V expression was quantified by DNA array. Before the study, participants were placed on a 1.2-g/kg/d protein diet, and metabolic acidosis was corrected.
  
  
  RESULTS
  During HD, plasma IL-6 levels increased from 7.54 +/- 2.24 to 27.86 +/- 4.94 pg/dL (P < 0.001). Complement component, IL-1, and TNF-alpha levels did not change significantly during HD. mRNA levels of caspase-3 (0.50 +/- 0.01 versus 0.81 +/- 0.04), annexin-V (0.94 +/- 0.06 versus 1.48 +/- 0.05; P < 0.001), ubiquitin (1.10 +/- 0.03 versus 1.44 +/- 0.03), and BCKAD-E2 (0.47 +/- 0.01 versus 0.81 +/- 0.04) increased in muscle during HD compared with pre-HD values (P < 0.001). mRNA levels of ubiquitin (0.62 +/- 0.03) and BCKAD-E2 (0.58 +/- 0.02) were greater in controls than pre-HD values (P < 0.05). There were significant positive correlations between plasma IL-6 levels and expression of caspase-3, ubiquitin, and BCKAD-E2 genes.
  
  
  CONCLUSIONS
  HD causes activation of cytokines, which may mediate the increase in gene expression of caspase-3, ubiquitin, and BCKAD-E2 in skeletal muscles.
authors.affiliation: Division of Nephrology University of New Mexico, Albuquerque, NM, USA. DRaj@salud.unm.edu
authors.forename: Dominic S C
authors.initials: DS
authors.lastname: Raj
authors.forename: Hemangini
authors.initials: H
authors.lastname: Shah
authors.forename: Vallabh O
authors.initials: VO
authors.lastname: Shah
authors.forename: Arny
authors.initials: A
authors.lastname: Ferrando
authors.forename: Arthur
authors.initials: A
authors.lastname: Bankhurst
authors.forename: Robert
authors.initials: R
authors.lastname: Wolfe
authors.forename: Philip G
authors.initials: PG
authors.lastname: Zager
mesh_terms: D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / Q000096:biosynthesis / Q000235:genetics; D000138:Acidosis / Q000209:etiology / Q000378:metabolism; D000328:Adult; D017209:Apoptosis; D001706:Biopsy; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics; D003131:Combined Modality Therapy; D003165:Complement System Proteins / Q000032:analysis; D016207:Cytokines / Q000097:blood; D018753:Diet, Protein-Restricted; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000150:complications; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000150:complications / Q000178:diet therapy / Q000628:therapy; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D006435:Renal Dialysis / Q000009:adverse effects; D025801:Ubiquitin / Q000096:biosynthesis / Q000235:genetics
chemical_list: D016207:Cytokines; D011506:Proteins; D012333:RNA, Messenger; D025801:Ubiquitin; D003165:Complement System Proteins; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases