title: HMG-CoA reductase activation and urinary pellet cholesterol elevations in acute kidney injury.
abstract: OBJECTIVE
  Experimental acute kidney injury (AKI) activates the HMG-CoA reductase (HMGCR) gene, producing proximal tubule cholesterol loading. AKI also causes sloughing of proximal tubular cell debris into tubular lumina. This study tested whether these two processes culminate in increased urinary pellet cholesterol content, and whether the latter has potential AKI biomarker utility.
  
  
  METHODS
  Urine samples were collected from 29 critically ill patients with (n = 14) or without (n= 15) AKI, 15 patients with chronic kidney disease, and 15 healthy volunteers. Centrifuged urinary pellets underwent lipid extraction, and the extracts were assayed for cholesterol content (factored by membrane phospholipid phosphate content). In vivo HMGCR activation was sought by measuring levels of RNA polymerase II (Pol II), and of a gene activating histone mark (H3K4m3) at exon 1 of the HMGCR gene (chromatin immunoprecipitation assay of urine chromatin samples).
  
  
  RESULTS
  AKI+ patients had an approximate doubling of urinary pellet cholesterol content compared with control urine samples (versus normal; P < 0.001). The values significantly correlated (r, 0.5; P < 0.01) with serum, but not urine, creatinine concentrations. Conversely, neither critical illness without AKI nor chronic kidney disease raised pellet cholesterol levels. Increased HMGCR activity in the AKI+ patients was supported by three- to fourfold increased levels of Pol II, and of H3K4m3, at the HMGCR gene (versus controls or AKI- patients).
  
  
  CONCLUSIONS
  (1) Clinical AKI, like experimental AKI, induces HMGCR gene activation; (2) increased urinary pellet cholesterol levels result; and (3) urine pellet cholesterol levels may have potential AKI biomarker utility. The latter will require future testing in a large prospective trial.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Ali Cm
authors.initials: AC
authors.lastname: Johnson
authors.forename: Lorraine B
authors.initials: LB
authors.lastname: Ware
authors.forename: Jonathan
authors.initials: J
authors.lastname: Himmelfarb
authors.forename: Richard A
authors.initials: RA
authors.lastname: Zager
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism*; D000328:Adult; D000368:Aged; D002784:Cholesterol / Q000652:urine*; D019175:DNA Methylation; D004789:Enzyme Activation; D005091:Exons; D005260:Female; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged
chemical_list: D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases