Effect Of FTY720 On Glomerulosclerosis And Expression Of Cell Cycle Regulatory Proteins In Subtotal Nephrectomized Rats

Object To study the effect of FTY720 on glomerulosclerosis and expression of cell cycle regulatory proteins in subtotal nephrectomized rats.Methods 24 rats were divided into sham-operation group, glomerulosclerosis model group and FTY720 treated glomerulosclerosis group, 8 rats in each groups. The rats in later two groups were subjected to 5/6 nephrectomy. After operation, rat in the treat group was fed with FTY720 at 0.5/mg﹒d for 12 weeks. Urine protein excretion was measured before opertion and 2w, 4w, 8w, 12w. Then, the rats were sacrificed and the left kidneys were subjected to pathological evaluation. The expression of collagenⅣ, fibronectin, and cyclinE, p21, p27 , PCNA were determined by immunohistochemistry methods.Results The daily urine protein (Up) in sham-operation group was (2.92±0.68 ) mg·d-1 before operation, and (3.72±0.61) mg·d-1 at 2w, (4.05±1.08) mg·d-1 at 8w, 4.29±0.77 )mg·d-1 at 12w. The model group showed higher daily urine protein excretion from 2w, (8.07±1.61) mg·d-1 and thereafter. At 12w, the Up increased to (28.6±12.21) mg·d-1 in model group, significantly higher than in sham-operation group (P<0.05). After treatment with FTY720, Up began to decrease from 4w after operation,(9.9±1.49)mg·d-1 at that time and(11.35±2.09)mg·d-1 at 12w, both were significantly lower than in model group (p<0.01). Scr level in sham-operation group was (27.85±8.23)μmol·L-1 before operation and(28.33±5.0)μmol·L-1 at 8w, (29.2±4.23)μmol·L-1 at 12w. The model group showed higher level of Scr from 8w, (61.08±4.28)μmol·L-1 at that time, (130.2±23.9)μmol·L-1at 12w, both were much higher than in sham-operation group (P<0.05). In FTY720 treated group, Scr level were (80.19±7.11)μmol·L-1 at 12w, much lower than in model group. The time course changes of BUN were similar to Scr in each group. Renal pathology and immunohistological evaluation showed that FTY720 could obviously inhibit the expressionof col-Ⅳand FN in glomeruli and attenuate the extent of glomerulosclerosis. Moreover, FTY720 could upregulate glomerular expression of p27 and downregulate glomerular expression of p21 and cyclinE. The expression of p21, cyclinE and PCNA were significantly lower in treatment group than in model group (P<0.05), but still higher than in sham-operation group (P<0.05). p27 expression in glomeruli was higher in treatment group than that in model group (P<0.05), and lower than that in normal group but without significant statistic difference.Conclusion FTY720 can diminish urine protein excretion and prevent glomerulosclerosis in subtotal nephrectomized rats. This protective effect is presumed to be associated with its role in downregulation of cyclinE expression and upregulation of p27 expression in glomerular cells, and inhibition of extracellular matrix accumulation in glomeruli.