OBJECTIVETo study the effect of FTY720 on glomerulosclerosis and expression of cell cycle regulatory proteins in subtotal nephrectomized rats.

METHODSTwenty-four rats were divided into sham-operation group, glomerulosclerosis model group and FTY720 treated glomerulosclerosis group with 8 rats in each group. The rats in the latter two groups were subjected to subtotal nephrectomy. After operation, the FTY720 treated group was fed with FTY720 at a dose of 0.5 mg/(kg x d) for 12 weeks. Urine protein excretion was measured before operation and 2 w, 4 w, 8 w and 12 w after operation. Then the rats were sacrificed and the left kidney was subjected to pathological evaluation. The expression of collagen IV, fibronectin, and cyclin E, p21, p27 were determined by immunohistochemical methods.

RESULTSCompared with the control group, the model group showed higher daily urine protein (Up) excretion from 2 w, (8.07 +/- 1.61) mg/d and thereafter. At 12 w, Up increased to (28.60 +/- 12.21) mg/d in model group, significantly higher than that in control group (P < 0.05). After treatment with FTY720, Up began to decrease from 4 w after operation, (9.90 +/- 1.49) mg/d at that time and (11.35 +/- 2.09) mg/d at 12 w, both were significantly lower than those in model group (P < 0.01). The model group showed higher level of serum creatinine from 8 w, (61.08 +/- 4.28) micromol/L at that time, (130.20 +/- 23.90) micromol/L at 12 w, both were much higher than those in control group (P < 0.05). In FTY720 treated group, serum creatinine level was (80.19 +/- 7.11) micromol/L at 12 w, much lower than that in model group. The changes of BUN were similar to those of creatinine in each group. Renal pathology and immunohistological evaluation showed that FTY720 could significantly inhibit the expression of collagen-IV and fibronectin in glomeruli and attenuate the extent of glomerulosclerosis. Moreover, FTY720 could upregulate glomerular expression of p21 and downregulate glomerular expression of p27 and cyclin E. The expression levels of p21 and cyclin E were significantly lower in treatment group than in model group (P < 0.05), but still higher than those in control group (P < 0.05). p27 expression in glomeruli was stronger in treatment group than that in model group (P < 0.05), and lower than that in normal group but the difference was not significant.

CONCLUSIONFTY720 can diminish urine protein excretion and prevent glomerulosclerosis in subtotally nephrectomized rats. This protective effect is presumed to be associated with its effect on expression of cell cycle regulatory proteins, and inhibition of extracellular matrix accumulation in glomeruli.