title: Myocardial preconditioning reduces kidney injury and apoptosis induced by myocardial ischaemia and reperfusion.
abstract: OBJECTIVE
  Acute kidney injury is a common and serious complication of cardiac surgery. Because its underlying mechanisms are unclear, there is no specific therapy to prevent or treat it. A regional transient ischaemia and reperfusion (I/R) may provide protection to distant tissue or organs, a phenomenon known as remote preconditioning. In this study, we investigated whether myocardial preconditioning (MPC) would reduce kidney injury and apoptosis induced by myocardial I/R, as well as the mechanisms involved.
  
  
  METHODS
  Myocardial I/R was induced by a 40-min occlusion of the left anterior descending artery and a 3-h reperfusion in anaesthetized Sprague-Dawley rats. MPC was elicited by two 10-min coronary artery occlusions and two 10-min reperfusions. A sham group received the same surgical procedures without coronary artery occlusion and reperfusion.
  
  
  RESULTS
  Compared with the sham group, myocardial I/R significantly increased the serum creatinine levels (1.15 ± 0.44 vs 0.54 ± 0.23 mg/dl, P < 0.05, mean ± standard deviation) and renal histological damage, indicating increased kidney injury. Kidney apoptosis was also significantly increased, as evidenced by the increase in the terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate (dUTP) nick-end labelling (TUNEL)-positive nuclei, clear DNA laddering and increased caspase-3 activation. Serum levels of tumour necrosis factor-α (TNF-α), interleukin-1 (IL-1) and interleukin-6 (IL-6) were significantly elevated, as were TNF-α levels in the kidneys. MPC significantly decreased myocardial infarct size (18.5 ± 3.1 vs 25.6 ± 2.1% of area at risk, P < 0.001). Additionally, MPC significantly reduced the serum creatinine level (0.65 ± 0.19 mg/dl, P < 0.05), renal histological damage and apoptosis. The increase in the serum levels of TNF-α, IL-1 and IL-6, and of TNF-α in the kidneys, was significantly inhibited. Western blot analysis found that MPC significantly increased Bcl-2 and decreased Bax in the kidneys. Phosphorylation of Akt and extracellular signal-regulated kinases 1 and 2 (ERK1/2) was significantly increased. Haemodynamics, area at risk and mortality did not differ significantly among the groups.
  
  
  CONCLUSIONS
  MPC significantly reduces kidney injury and apoptosis induced by myocardial I/R. The underlying mechanisms might be related to inhibition of both the extrinsic and intrinsic pathways of apoptosis, possibly via inhibition of TNF-α production, modulation of Bcl-2 and Bax and activation of Akt and ERK1/2.
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, National Yang-Ming University School of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan chhuang@vghtpe.gov.tw.
authors.forename: Cheng-Hsiung
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Chang-Chi
authors.initials: CC
authors.lastname: Lai
authors.affiliation: Department of Pathology and Laboratory Medicine, National Yang-Ming University School of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: An-Han
authors.initials: AH
authors.lastname: Yang
authors.affiliation: Institute of Hospital and Health Care Administration, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Shu-Chiung
authors.initials: SC
authors.lastname: Chiang
mesh_terms: D058186:Acute Kidney Injury / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000032:analysis; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D019157:Ischemic Preconditioning, Myocardial; D007668:Kidney / Q000737:chemistry / Q000473:pathology; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications*; D015428:Myocardial Reperfusion Injury / Q000150:complications*; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000097:blood; D051028:bcl-2-Associated X Protein / Q000032:analysis
chemical_list: D007375:Interleukin-1; D015850:Interleukin-6; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3
keywords: Acute kidney injury; Apoptosis; Myocardial ischaemia and reperfusion; Myocardial preconditioning; Prosurvival kinases