Long-term protective effect of UR-12670 after warm renal ischemia in uninephrectomized rats

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 pot ent orally active PAF antagonist UR-12670 in warm ischemic uninephrectomize d 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 7t h 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 S-E). Two mor e groups (ischemic and UR treated) served to evaluate the UR-12670-protecti ve effect on ischemic acute renal failure at one week. Results. UR-12670 administration exerted functional and morphological prote ction against post-ischemic acute renal failure. The ischemic untreated (SI K) group developed progressive proteinuria from week 12. The onset of prote inuria in ischemic UR-12670-treated groups was delayed to the 24th week, an d it was significantly lower than in SIK group throughout the study. Only S IK and ischemic-treated UR 0-7 rats presented with chronic renal failure, a s shown by creatinine, creatinine clearance, glomerular filtration rate (GF R), and renal plasma Row (GFR 52 weeks: SK, 2525 +/- 267; SIK, 992 +/- 149; UR 0-7, 1551 +/- 385 mu l/min). Kidneys from the short-term treated group (UR 0-7) showed a reduction of glomerulosclerosis (SK, 14.3 +/- 3.7; SIK, 7 5.7 +/- 7.7; UR 0-7, 41.5 +/- 8.5%) and vascular myointimal hyperplasia, bu t 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 S-E, 2410 +/- 208 mu l/min). In these groups, glomerulosclerosis (UR 0-E, 32.8 +/- 5.8; U R 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 hyperpla sia were significantly lower than in the ischemic untreated group. By in si tu hybridization, an increase of transforming growth factor-pi mRNA express ion 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 clea r reduction of transforming growth factor-pi mRNA-positive glomerular cells . Conclusion. The chronic administration of the PAF antagonist UR-12670 atten uates the long-term effects of ischemia-reperfusion injury in uninephrectom ized 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.