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KMID : 0043320100330020275
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Archives of Pharmacal Research
2010 Volume.33 No. 2 p.275 ~ p.284
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LSKL, a Peptide Antagonist of Thrombospondin-1, Attenuates Renal Interstitial Fibrosis in Rats with Unilateral Ureteral Obstruction
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Fan Jun-Ming
Xie Xi-sheng
Li Fei-yan
Deng Yao
Li Zi
Liu Heng-Chuan
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Abstract
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The effects of LSKL, the peptide antagonist of thrombospondin-1 (TSP-1), on renal interstitial fibrosis in rats subjected to unilateral ureteral obstruction (UUO) were investigated. Rats were divided randomly into three groups (n = 20 each): UUO group, sham-operation group and UUO plus LSKL treatment group. Collagen deposition was studied using histopathology and reverse transcription polymerase chain reaction analysis (RT-PCR). TSP-1, transforming growth factor beta 1 (TGF-β1), phosphorylated Smad2 (pSsmad2) and α-smooth muscle actin (α-SMA) in the kidney were measured using immunocytochemistry, western blotting analysis, RT-PCR and enzyme-linked immunosorbent assay. Biochemical analyses in the serum and urine were made. Histopathology showed severe tubular dilatation and atrophy, interstitial inflammation and collagen accumulation after surgery and LSKL significantly inhibited interstitial fibrosis including tubular injury as well as collagen deposition. The protein and mRNA levels of TSP-1 increased notably at different time point and significantly decreased in the presence of LSKL. The expression of TGF-β1 and pSmad2 were upregulated in the obstructed kidney and substantially suppressed by LSKL treatment. Myofibroblast accumulation could be alleviated after administration of LSKL. Biochemical parameters did not show differences among the three groups. As TSP-1 is the major activator of TGF-β1, we demonstrate that LSKL can attenuate renal interstitial fibrosis in vivo by preventing TSP-1-mediated TGF-β1 activation.
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KEYWORD
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LSKL, Renal interstitial fibrosis, Transforming growth factor-β1, Thrombospondin-1, Myofibroblast
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