Effects of low molecular weight heparin in obstructed kidneys:: decrease of collagen, fibronectin and TGF-β, and increase of chondroitin/dermatan sulfate proteoglycans and macrophage infiltration
Effects of low molecular weight heparin in obstructed kidneys:: decrease of collagen, fibronectin and TGF-β, and increase of chondroitin/dermatan sulfate proteoglycans and macrophage infiltration
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DOI：
10.1093/ndt/gfk076
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发表时间：
2006-05-01
影响因子：
6.1
通讯作者：
Leite, M
中科院分区：
文献类型：
--
作者：
Pecly, IMD;Gonçalves, RG;Leite, M
背景肝素在不同的肾病实验模型中发挥有益作用，如通过肝素治疗后肾脏结构形态的保留所观察到的。在此，我们研究了肝素在单侧输尿管梗阻后肾脏疾病进展中的保护作用所涉及的分子和细胞事件。将36只大鼠分为6组：C组（对照组）不进行任何手术操作; S组（假手术组）进行手术操作但不进行输尿管结扎; UUO组进行输尿管梗阻并且不接受治疗; UUO + S组进行输尿管梗阻并且皮下（s.c.）UUO + H组在输尿管梗阻后皮下注射低分子量肝素（LMW-Hep; 4 mg/kg），UUO + H组在输尿管梗阻后皮下注射LMW-Hep; C + H组不接受任何手术操作，并接受LMW-Hep（4 mg/kg）s.c.每天一次。14 d后，采用免疫组化和生化技术检测肾脏胶原、纤维连接蛋白、总糖胺聚糖（GAGS）、硫酸软骨素/硫酸皮肤素蛋白聚糖（CS/DSPGs）、转化生长因子-β（TGF-β）含量及细胞浸润情况。UUO组胶原、纤维连接蛋白、总GAGS、CS/DSPGs、TGF-β和细胞浸润显著增加。与UUO组相比，UUO + H组胶原、纤维连接蛋白和TGF-β减少，但总GAGS、CS/DSPGs含量和巨噬细胞浸润增加。LMW-Hep通过下调胶原蛋白、纤连蛋白和TGF-β的合成来减少阻塞肾脏中的纤维化。CS/DSPG过度产生和LMW-Hep给药后细胞浸润增加的机制仍有待阐明。
Background. Heparin exerts beneficial effects in different experimental models of nephropathy, as observed by the preservation of the structural morphology of the kidney after heparin therapy. Here we investigate molecular and cellular events involved in the protective effects of heparin in the progression of renal disease after unilateral ureteral obstruction.Methods. Thirty-six rats were divided into six groups: group C (control) was not subjected to any surgical manipulation; group S (sham) was subjected to surgical manipulation but without ureteral ligation; group UUO was subjected to ureteral obstruction and received no treatment; group UUO + S was subjected to ureteral obstruction and received saline subcutaneously (s.c.) once daily; group UUO + H was subjected to ureteral obstruction and received low molecular weight heparin (LMW-Hep; 4 mg/kg) s.c. once daily; and group C + H was not subjected to any surgical manipulation and received LMW-Hep (4 mg/kg) s.c. once daily. After 14 days, the content of collagen, fibronectin, total glycosaminoglycans (GAGS), chondroitin sulfate/dermatan sulfate proteoglycans (CS/DSPGs), transforming groth factor-beta (TGF-beta) and cellular infiltration were determined in the kidneys by immunohistochemical and biochemical techniques.Results. Collagen, fibronectin, total GAGS, CS/DSPGs, TGF-beta and cellular infiltration increased significantly in group UUO. LMW-Hep treatment reduced collagen, fibronectin and TGF-beta, but induced an increase in the content of total GAGS, CS/DSPGs and macrophage infiltration in group UUO + H when compared with group UUO.Conclusions. LMW-Hep diminishes fibrosis in obstructed kidneys by downregulating the synthesis of collagen, fibronectin and TGF-beta. The mechanisms underlying the overproduction of CS/DSPGs and the increase in cellular infiltration upon LMW-Hep administration remain to be elucidated.