ABSTRACT
PURPOSE: This study was undertaken to investigate the effect of a p38 mitogen-activated protein kinase (p38 MAPK) inhibitor, FR167653, on urinary albumin excretion and on the expression of slit diaphragm-associated proteins in diabetic rats. METHODS: Thirty-two Sprague-Dawley rats were injected with diluent [control (C), N=16] or streptozotocin intraperitoneally (DM, N=16). Eight rats from each group were treated with 5 mg/kg/day FR 167653 (C+FR, DM+FR) for 6 weeks. At the time of sacrifice, 24-hour urinary albumin excretion was determined by ELISA. Glomerular nephrin, P-cadherin, and ZO-1 mRNA and protein expression were determined by real-time PCR and Western blot, respectively, with sieved glomeruli. RESULTS: Urinary albumin excretion was significantly higher in DM compared to C rats, and this increase in albuminuria was significantly inhibited by the administration of FR167653 in DM rats. Glomerular phospho-p38 MAPK protein expression was significantly increased in DM rats compared to C rats, and FR167653 treatment significantly attenuated the increase in phospho-p38 MAPK expression in DM glomeruli. Nephrin mRNA and protein expression were higher in 6-week DM compared to C glomeruli, and these increases were significantly abrogated with FR167653 treatment in DM rats. In contrast, FR167653 had no effects on the decrease in P-cadherin expression and the increase in ZO-1 expression observed in DM glomeruli. CONCLUSION: These findings suggest that FR167653, a p38 MAPK inhibitor, reduce the amount of albuminuria in early diabetic nephropathy, and this anti-proteinuric effect seems to be related with the change of glomerular nephrin expression.
Subject(s)
Animals , Rats , Albuminuria , Blotting, Western , Cadherins , Diabetic Nephropathies , Enzyme-Linked Immunosorbent Assay , Membrane Proteins , p38 Mitogen-Activated Protein Kinases , Protein Kinases , Proteins , Pyrazoles , Pyridines , Rats, Sprague-Dawley , Real-Time Polymerase Chain Reaction , RNA, Messenger , StreptozocinABSTRACT
Recently we reported that the inhibitor of <i>p</i>38 mitogen-activated protein kinase, FR-167653 (Fujisawa Pharm. Co., Ltd., Osaka) may suppress postoperative intimal hyperplasia. In this study we evaluated the best dosage and phase for administration of FR-167653, in order to clarify its mechanism in the postoperative treatment of intimal hyperplasia. Twenty-one Lewis male rats (484±5g) were studied. The epigastric vein graft was interposed into the common femoral artery. The rats were divided into four groups according to the dosage and phase of administration of FR-167653: group I (<i>n</i>=5) with 2.0μg/g of FR-167653 immediately before bypass, group T (<i>n</i>=5) with 2.0μg/g immediately before bypass and 2 weeks after bypass, group D (<i>n</i>=5) with 4.0μg/g immediately before bypass, and the control group (<i>n</i>=6) with the same dose of saline. The intimal areas of vein grafts were measured at 4 weeks postoperatively. The mean intimal areas in group I, T and D were significantly decreased compared with the control group, especially in group D (0.05±0.02mm<sup>2</sup> vs. 0.43±0.05mm<sup>2</sup>, <i>p</i><0.001). These results suggest that FR-167653 can suppress the postoperative intimal hyperplasia that occurs with interposition of vein grafts in rats.
ABSTRACT
Recently we reported that tumor necrosis factor-α (TNF-α) mRNA expression and the development of postoperative intimal hyperplasia (IH) is different in rat epigastric vein interposition graft, compared to femoral artery re-anastomosis. We evaluated whether a TNF-α suppressive agent, FR-167653 (Fujisawa Pharm. Co., Ltd., Osaka) could suppress IH or not. Eleven Lewis male rats (480±8g) were studied. The epigastric vein graft was interposed into the common femoral artery. They were divided into two groups: group FR (<i>n</i>=5) with 2.0μg/g of FR-167653, and group C (<i>n</i>=6) with same dose of saline instead of FR-167653. The intimal areas of vein grafts were measured at 4 weeks postoperatively. The mean intimal area in group FR was significantly decreased, compared with group C (0.160±0.057mm<sup>2</sup> vs. 0.434±0.045mm<sup>2</sup>, <i>p</i><0.01). These results suggest that the TNF-α suppressive agent FR-167653 may suppress the postoperative intimal hyperplasia that occurs on the interposition vein graft in rats.