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KMID : 0359920080270030280
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Korean Journal of Nephrology
2008 Volume.27 No. 3 p.280 ~ p.289
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The Effect of FR167653, p38 Mitogen-Activated Protein Kinase (MAPK) Inhibitor, on the Expression of Slit Diaphragm-Associated Proteins in Experimental Diabetic Nephropathy
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Ryu Dong-Ryeol
Yoo Tae-Hyun
Jung Dong-Sub
Kwak Seung-Jae
Park Je-hyun
Lee Sun-Ha
Li Jin-Ji
Ryu Jung-Hwa
Yu Min-A
Kim Seung-Jung
Kang Duk-Hee
Choi Kyu-Bok
Yoon Kyun-Il
Han Dae-Suk
Kang Shin-Wook
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Abstract
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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.
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KEYWORD
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Diabetic nephropathy, p38 mitogen-activated protein kinases, FR167653
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