No abstract available.
Acetic Acids/adverse effects/pharmacology ; Anticonvulsants/adverse effects/*pharmacology ; Carbamazepine/adverse effects/analogs & derivatives/pharmacology ; Clinical Trials ; Forecasting ; Fructose/adverse effects/analogs & derivatives/pharmacology ; Human ; Isoxazoles/adverse effects/pharmacology ; Propylene Glycols/adverse effects/pharmacology ; Triazines/adverse effects/pharmacology ; Vigabatrin ; gamma-Aminobutyric Acid/adverse effects/analogs & derivatives/pharmacology

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.

Animals ; Cell Cycle Proteins ; biosynthesis ; Disease Models, Animal ; Fingolimod Hydrochloride ; Glomerulosclerosis, Focal Segmental ; metabolism ; pathology ; therapy ; Immunosuppressive Agents ; pharmacology ; therapeutic use ; Kidney ; pathology ; surgery ; Male ; Nephrectomy ; adverse effects ; Postoperative Period ; Propylene Glycols ; pharmacology ; therapeutic use ; Rats ; Rats, Sprague-Dawley ; Sphingosine ; analogs & derivatives ; pharmacology ; therapeutic use

Higher levels of body fat are associated with an increased risk for development numerous adverse health conditions. FTY720 is an immune modulator and a synthetic analogue of sphingosine 1-phosphate (S1P), activated S1P receptors and is effective in experimental models of transplantation and autoimmunity. Whereas immune modulation by FTY720 has been extensively studied, other actions of FTY720 are not well understood. Here we describe a novel role of FTY720 in the prevention of obesity, involving the regulation of adipogenesis and lipolysis in vivo and in vitro. Male C57B/6J mice were fed a standard diet or a high fat diet (HFD) without or with FTY720 (0.04 mg/kg, twice a week) for 6 weeks. The HFD induced an accumulation of large adipocytes, down-regulation of phosphorylated AMP-activated protein kinase alpha (p-AMPKalpha) and Akt (p-Akt); down-regulation of hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL) and perilipin mRNA as well as up-regulation of phosphorylated HSL (p-HSL, Ser563) and glycogen synthase kinase 3 alpha/beta (p-GSK3alpha/beta). All these effects were blunted by FTY720 treatment, which inhibited adipogenesis and promoted lipolysis. Also, FTY720 significantly decreased lipid accumulation in maturing preadipocytes. FTY720 down-regulated the transcriptional levels of the PPARgamma, C/EBPalpha and adiponectin, which are markers of adipogenic differentiation. FTY720 significantly increased the release of glycerol and the expression of the HSL, ATGL and perilipin, which are regulators of lipolysis. These results show that FTY720 prevented obesity by modulating adipogenesis and lipolysis, and suggest that FTY720 is used for the treatment of obesity.
3T3-L1 Cells ; AMP-Activated Protein Kinases/metabolism ; Adipocytes/*drug effects/physiology ; Adipogenesis/drug effects ; Animals ; Anti-Obesity Agents/*pharmacology/therapeutic use ; Antigens, Differentiation/genetics/metabolism ; Carrier Proteins/genetics/metabolism ; Cell Size ; Diet, High-Fat/adverse effects ; Disease Models, Animal ; Enzyme Activation ; Gene Expression Regulation, Enzymologic/drug effects ; Glycogen Synthase Kinase 3/genetics/metabolism ; Lipase/genetics/metabolism ; Lipolysis/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Obesity/etiology/metabolism/*prevention & control ; Phosphoproteins/genetics/metabolism ; Phosphorylation ; Propylene Glycols/*pharmacology/therapeutic use ; Protein Processing, Post-Translational ; Proto-Oncogene Proteins c-akt/metabolism ; Sphingosine/*analogs & derivatives/pharmacology/therapeutic use ; Sterol Esterase/metabolism