title: Long-term protective effect of UR-12670 after warm renal ischemia in uninephrectomized rats.
abstract: BACKGROUND
  The phospholipid platelet-activating factor (PAF) participates in the pathogenesis of renal ischemia/reperfusion injury, and in vitro, it induces synthesis of extracellular matrix proteins by mesangial and tubular epithelial cells. This study investigated the long-term effects of the potent orally active PAF antagonist UR-12670 in warm ischemic uninephrectomized rats, which was given according to different therapeutic schedules.
  
  
  METHODS
  Uninephrectomized male Sprague-Dawley rats were divided into five groups and were followed for 52 weeks: rats without ischemia (SK); ischemic kidney for 60 minutes (SIK); ischemic kidney and UR-12670 from 0 to the 7th day (UR 0-7); ischemic kidney and UR-12670 from day 0 to 52 weeks (UR 0-E); and ischemic kidney and UR-12670 from day 8 to week 52 (UR 8-E). Two more groups (ischemic and UR treated) served to evaluate the UR-12670-protective effect on ischemic acute renal failure at one week.
  
  
  RESULTS
  UR-12670 administration exerted functional and morphological protection against post-ischemic acute renal failure. The ischemic untreated (SIK) group developed progressive proteinuria from week 12. The onset of proteinuria in ischemic UR-12670-treated groups was delayed to the 24th week, and it was significantly lower than in SIK group throughout the study. Only SIK and ischemic-treated UR 0-7 rats presented with chronic renal failure, as shown by creatinine, creatinine clearance, glomerular filtration rate (GFR), and renal plasma flow (GFR 52 weeks: SK, 2525 +/- 267; SIK, 992 +/- 149; UR 0-7, 1551 +/- 385 microliter/min). Kidneys from the short-term treated group (UR 0-7) showed a reduction of glomerulosclerosis (SK, 14.4 +/- 3.7; SIK, 75.7 +/- 7.7; UR 0-7, 41. 5 +/- 8.5%) and vascular myointimal hyperplasia, but the tubulointerstitial damage (tubulointerstitial score: SK, 0.2 +/- 0. 2; SIK, 4.4 +/- 0.5; UR 0-7, 3.7 +/- 0.7) was similar to that in the ischemic untreated group. Long-term ischemic treated rats (UR 0-E, UR 8-E) did not develop chronic renal failure (GFR: UR 0-E, 2059 +/- 314; UR 8-E, 2410 +/- 208 microliter/min). In these groups, glomerulosclerosis (UR 0-E, 32.8 +/- 5.8; UR 8-E, 24.3 +/- 3.0%), tubulointerstitial damage (tubulointerstitial score: UR 0-E, 2.1 +/- 0.5; UR 8-E, 1.9 +/- 0.3) and vascular myointimal hyperplasia were significantly lower than in the ischemic untreated group. By in situ hybridization, an increase of transforming growth factor-beta1 mRNA expression in glomerular and tubular cells was observed in ischemic untreated and ischemic treated UR 0-7 rats. UR-12670 long-term treated rats showed a clear reduction of transforming growth factor-beta1 mRNA-positive glomerular cells.
  
  
  CONCLUSIONS
  The chronic administration of the PAF antagonist UR-12670 attenuates the long-term effects of ischemia-reperfusion injury in uninephrectomized rats. The beneficial effect of this agent, even when given beyond the initial ischemia/reperfusion injury, suggests that PAF plays a role in the mechanisms of progression to late renal damage in this model.
authors.affiliation: Department of Nephrology, Hospital de Bellvitge, L'Hospitalet, Medicine Department, University of Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Torras
authors.forename: J M
authors.initials: JM
authors.lastname: Cruzado
authors.forename: M
authors.initials: M
authors.lastname: Riera
authors.forename: E
authors.initials: E
authors.lastname: Condom
authors.forename: N
authors.initials: N
authors.lastname: Duque
authors.forename: I
authors.initials: I
authors.lastname: Herrero
authors.forename: M
authors.initials: M
authors.lastname: Merlos
authors.forename: L
authors.initials: L
authors.lastname: Espinosa
authors.forename: N
authors.initials: N
authors.lastname: Lloberas
authors.forename: J
authors.initials: J
authors.lastname: Egido
authors.forename: J M
authors.initials: JM
authors.lastname: Grinyó
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy; D000818:Animals; D007093:Imidazoles / Q000627:therapeutic use*; D007511:Ischemia / Q000188:drug therapy*; D007668:Kidney / Q000098:blood supply*; D008297:Male; D009392:Nephrectomy; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D011725:Pyridines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D007093:Imidazoles; D010972:Platelet Activating Factor; D011725:Pyridines; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C097826:UR 12670