title: Renal ischemia-reperfusion injury in the rat is prevented by a novel immune modulation therapy.
abstract: BACKGROUND
  Vasogen Inc.'s (Mississauga, Ontario, Canada) immune modulation therapy (IMT) is a therapy in which cells from the patient's own blood are modified by ex vivo exposure to specific physicochemical stressors, including oxidation, ultraviolet (UV) light, and an elevated temperature. The therapy has been shown to have a beneficial effect in models of inflammation and vascular diseases. This study tested the hypothesis that IMT can prevent renal ischemia-reperfusion (I/R) injury in rats.
  
  
  METHODS
  Whole blood was collected from syngeneic age-matched donors by cardiac puncture. It was treated with a combination of controlled physiochemical stressors consisting of elevated temperature, a gas mixture of medical oxygen containing ozone, and UV light. The treated blood (150 microL) was injected in the gluteal muscle. Control animals received the same volume of untreated blood or physiological saline. Transient (45 or 60 minutes) left-renal ischemia was produced with simultaneous contralateral nephrectomy in treated and control spontaneously hypertensive rats (SHR). Young and old male and female rats were studied. Plasma creatinine, diuresis, and the survival rates of each group were compared. Renal apoptosis-necrosis was estimated by DNA laddering, histology, and in situ terminal deoxynucleotidyl transferase assay. mRNA levels of several regulators of apoptosis-regeneration were determined in control and postischemic kidneys by Northern blotting.
  
  
  RESULTS
  IMT pretreatment of SHR significantly reduced renal I/R injury compared with equivalent placebo treatments consisting of untreated blood- or saline-injected SHR, as evidenced by a significant increase of the survival rate curves in young and old male SHR, which correlated with 24-hour postischemic diuresis. The increases in plasma creatinine following renal I/R were significantly lower in IMT-treated young male and old female SHR compared with saline or untreated blood-injected controls. Dilution analysis showed that the protective effect of treated blood was lost by dilution. Loss of epithelial cells was reduced in IMT-treated rats, with a significant decline in the peak of apoptosis 12 hours after acute ischemic renal injury. IMT did not modify the pattern of mRNA levels of several genes involved in the inflammation and regeneration processes.
  
  
  CONCLUSIONS
  Our data demonstrate that IMT prevents the destruction of kidney tissue and the resulting animal death caused by renal I/R injury.
authors.affiliation: Centre de recherche, Centre hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Johanne
authors.initials: J
authors.lastname: Tremblay
authors.forename: Huifang
authors.initials: H
authors.lastname: Chen
authors.forename: Junzheng
authors.initials: J
authors.lastname: Peng
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Kunes
authors.forename: Minh Diem
authors.initials: MD
authors.lastname: Vu
authors.forename: Shant
authors.initials: S
authors.lastname: Der Sarkissian
authors.forename: Denis
authors.initials: D
authors.lastname: deBlois
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Bolton
authors.forename: Louis
authors.initials: L
authors.lastname: Gaboury
authors.forename: Vladimir
authors.initials: V
authors.lastname: Marshansky
authors.forename: Elodie
authors.initials: E
authors.lastname: Gouadon
authors.forename: Pavel
authors.initials: P
authors.lastname: Hamet
mesh_terms: D000818:Animals; D005260:Female; D015870:Gene Expression; D007167:Immunotherapy / Q000379:methods*; D007511:Ischemia / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D019194:Ischemic Preconditioning; D007668:Kidney / Q000098:blood supply*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D015427:Reperfusion Injury / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D014409:Tumor Necrosis Factor-alpha