title: Humoral signalling compounds in remote ischaemic preconditioning of the kidney, a role for the opioid receptor.
abstract: BACKGROUND
  Renal ischaemia-reperfusion injury (IRI) is a common clinical problem associated with significant mortality and morbidity. One strategy to reduce this damage is remote ischaemic preconditioning (RIPC), in which brief ischaemia of a limb protects the kidney against a prolonged ischaemic insult. The mechanism of renal RIPC has not yet been elucidated. Here, we address the gap in our understanding of renal RIPC signalling, using a rat model of renal IRI and RIPC by brief hind limb ischaemia.
  
  
  METHODS
  Rats were treated with either no RIPC, RIPC+vehicle or RIPC+ an inhibitor or antagonist of one of the following candidate signalling molecules: noradrenalin, cannabinoids, glucocorticoids, inducible nitric oxide synthase, calcitonin gene-related peptide, ganglion-mediated signalling, haem oxygenase and free radicals. Subsequently, the animals underwent 25 min of renal ischaemia and 2 days of reperfusion, after which renal function and damage were assessed.
  
  
  RESULTS
  RIPC by three 4 min cycles of hind limb ischaemia effectively reduced renal IRI. Pre-treatment with the opioid receptor antagonist naloxone completely blocked this protective effect, when compared with animals treated with RIPC+vehicle; serum creatinine and urea increased (307.8±43.7 versus 169.5±16.7 µmol/L and 42.2±4.9 versus 27.6±2.2 mmol/L, respectively), as did the renal histological damage (score 4.2±0.7 versus 2.8±0.5) and expression of kidney injury molecule-1 (KIM-1; relative-fold increase in mRNA expression 164±18 versus 304±33). All other antagonists were without effect.
  
  
  CONCLUSIONS
  Renal RIPC by brief hind limb ischaemia may be the result of endorphin release from the hind limb. The importance of opioid signalling in renal RIPC provides vital clues for its successful translation to the clinical setting.
authors: Department of Pharmacology and Toxicology, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands. k.wever@chir.umcn.nl
authors: Kimberley E
authors: KE
authors: Wever
authors: Rosalinde
authors: R
authors: Masereeuw
authors: Frank A
authors: FA
authors: Wagener
authors: Vivienne G M
authors: VG
authors: Verweij
authors: Janny G P
authors: JG
authors: Peters
authors: Jeanne C L M
authors: JC
authors: Pertijs
authors: J Adam
authors: JA
authors: Van der Vliet
authors: Michiel C
authors: MC
authors: Warlé
authors: Gerard A
authors: GA
authors: Rongen
mesh_terms: D000701:Analgesics, Opioid / Q000032:analysis / Q000494:pharmacology*; D000818:Animals; D015415:Biomarkers / Q000032:analysis*; D004723:Endorphins / Q000378:metabolism; D006614:Hindlimb / Q000503:physiopathology*; D019194:Ischemic Preconditioning; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D011957:Receptors, Opioid / Q000378:metabolism*; D015427:Reperfusion Injury / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D015415:Biomarkers; D004723:Endorphins; D012333:RNA, Messenger; D011957:Receptors, Opioid
keywords: animal model; ischaemia–reperfusion injury; opioids; remote ischaemic preconditioning