title: Renal kallikrein excretion and epigenetics in human acute kidney injury: expression, mechanisms and consequences.
abstract: BACKGROUND
  Renal kallikrein (KLK1) synthesis and urinary excretion are reportedly diminished during AKI (acute kidney injury) in animal models, and provision of kallikrein abrogates renal injury in this setting, but data in human AKI is limited. Therefore we first examined KLK1 renal excretion in human AKI, and then probed potential endocrine and epigenetic mechanisms for its alterations.
  
  
  METHODS
  KLK1 enzymatic activity excretion was evaluated in urine from patients with established or incipient AKI, versus healthy/non-hospital as well as ICU controls. Endocrine control of KLK1 excretion was then probed by catecholamine and aldosterone measurements in established AKI versus healthy controls. To examine epigenetic control of KLK1 synthesis, we tested blood and urine DNA for changes in promoter CpG methylation of the KLK1 gene, as well as LINE-1 elements, by bisulfite sequencing.
  
  
  RESULTS
  Patients with early/incipient AKI displayed a modest reduction of KLK1 excretion, but unexpectedly, established AKI displayed substantially elevated urine KLK1 excretion, ~11-fold higher than healthy controls, and ~3-fold greater than ICU controls. We then probed potential mechanisms of the change. Established AKI patients had lower SBP, higher heart rate, and higher epinephrine excretion than healthy controls, though aldosterone excretion was not different. Promoter KLK1 CpG methylation was higher in blood than urine DNA, while KLK1 methylation in blood DNA was significantly higher in established AKI than healthy controls, though KLK1 methylation in urine tended to be higher in AKI, directionally consistent with earlier/incipient but not later/established changes in KLK1 excretion in AKI. On multivariate ANOVA, AKI displayed coordinate changes in KLK1 excretion and promoter methylation, though directionally opposite to expectation. Control (LINE-1 repetitive element) methylation in blood and urine DNA was similar between AKI and controls.
  
  
  CONCLUSIONS
  Unexpectedly, increased KLK1 excretion in AKI patients was found; this increase is likely to be due in part to increments in adrenergic tone during BP depression. Epigenetic changes at KLK1 may also play a role in early changes of KLK1 expression and thus AKI susceptibility or recovery.
authors.affiliation: Department of Nephrology, Inje University, Busan, South Korea.
authors.forename: Sun Woo
authors.initials: SW
authors.lastname: Kang
authors.forename: Pei-An Betty
authors.initials: PA
authors.lastname: Shih
authors.forename: Roy O
authors.initials: RO
authors.lastname: Mathew
authors.forename: Manjula
authors.initials: M
authors.lastname: Mahata
authors.forename: Nilima
authors.initials: N
authors.lastname: Biswas
authors.forename: Fangwen
authors.initials: F
authors.lastname: Rao
authors.forename: Liying
authors.initials: L
authors.lastname: Yan
authors.forename: Josee
authors.initials: J
authors.lastname: Bouchard
authors.forename: Rakesh
authors.initials: R
authors.lastname: Malhotra
authors.forename: Ashita
authors.initials: A
authors.lastname: Tolwani
authors.forename: Srikrishna
authors.initials: S
authors.lastname: Khandrika
authors.forename: Ravindra L
authors.initials: RL
authors.lastname: Mehta
authors.forename: Daniel T
authors.initials: DT
authors.lastname: O'Connor
mesh_terms: D058186:Acute Kidney Injury / Q000201:enzymology* / Q000235:genetics*; D000328:Adult; D000368:Aged; D001483:Base Sequence; D015415:Biomarkers / Q000652:urine; D015331:Cohort Studies; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007362:Intensive Care Units; D007610:Kallikreins / Q000096:biosynthesis / Q000235:genetics* / Q000652:urine*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011446:Prospective Studies; D015854:Up-Regulation / Q000235:genetics
chemical_list: D015415:Biomarkers; D007610:Kallikreins