Research Articles Drug Actions

Archives of Pharmacal Research

, Volume 33, Issue 2, pp 275-284

First online:

LSKL, a peptide antagonist of thrombospondin-1, attenuates renal interstitial fibrosis in rats with unilateral ureteral obstruction

  • Xi-sheng XieAffiliated withDepartment of Nephrology, West China Hospital of Sichuan University
  • , Fei-yan LiAffiliated withDepartment of Respiratory Medicine, The First Affiliated Hospital of Medical College of Xi’an Jiaotong University
  • , Heng-chuan LiuAffiliated withDepartment of Medicine Technology, West China School of Public Health, Sichuan University
  • , Yao DengAffiliated withDepartment of Nephrology, West China Hospital of Sichuan University
  • , Zi LiAffiliated withDepartment of Nephrology, West China Hospital of Sichuan University
  • , Jun-ming FanAffiliated withDepartment of Nephrology, West China Hospital of Sichuan University Email author 

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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.

Key words

LSKL Renal interstitial fibrosis Transforming growth factor-β1 Thrombospondin-1 Myofibroblast