LSKL, a peptide antagonist of thrombospondin-1, attenuates renal interstitial fibrosis in rats with unilateral ureteral obstruction.
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-beta1), phosphorylated Smad2 (pSsmad2) and alpha-smooth muscle actin (alpha-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-beta1 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-beta1, we demonstrate that LSKL can attenuate renal interstitial fibrosis in vivo by preventing TSP-1-mediated TGF-beta1 activation.
Xie
Xi-sheng
XS
Department of Nephrology, West China Hospital of Sichuan University, No.37, Guoxuexiang, Wuhou, Chengdu 610041, China.
Li
Fei-yan
FY
Liu
Heng-chuan
HC
Deng
Yao
Y
Li
Zi
Z
Fan
Jun-ming
JM
D000199:Actins / Q000378:metabolism; D000818:Animals; D003094:Collagen / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects; D005355:Fibrosis / Q000473:pathology / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009395:Nephritis, Interstitial / Q000473:pathology / Q000517:prevention & control*; D010455:Peptides / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D019700:Thrombospondin 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014517:Ureteral Obstruction / Q000150:complications*
D000199:Actins; D003094:Collagen; D010455:Peptides; D051899:Smad2 Protein; D019700:Thrombospondin 1; D053773:Transforming Growth Factor beta1; C487834:Leu-Ser-Lys-Leu peptide; C498862:Acta2 protein, rat