Low molecular weight heparin (LMWH) improves peritoneal function and inhibits peritoneal fibrosis possibly through suppression of HIF-1α, VEGF and TGF-β1.
BACKGROUND
Peritoneal fibrosis is the major cause of ultrafiltration failure, and intraperitoneal administration of Low Molecular Weight Heparin (LMWH) was reported to protect peritoneal function. But the exact mechanism of its influence on peritoneal structure and function is still unknown.


METHODS
A fibrosis model of rat was established by intraperitoneal (IP) administration of PD fluid and Erythromycin Lactobionate. Fifty-two rats were randomly divided into 6 groups: (1) normal control group (CON, n = 6); (2) normal saline group (NS, n = 10); (3) high-glucose group (GLU, n = 10); (4) heparin group (HEP, n = 6); (5) low dose LMWH group (LLMWH, n = 10); (6) high dose LMWH group (HLMWH, n = 10). Two hour peritoneal equilibration test was performed after 28 days of intervention. The peritoneum, mesentery and omentum were harvested, and evaluated by Hematoxylin-Eosin and Masson Trichrome staining. The expressions of HIF-1α, VEGF and TGF-β1 in parietal peritoneum were detected by IHC and RT-PCR (Reverse Transcriptase Polymerase Chain Reaction).


RESULTS
Compared with group CON and NS, ultrafiltration volume and D2/D0 glucose in group GLU decreased significantly, D/Purea (Dialysate-Plasma ratio of urea), D/Palb (Dialysate-Plasma ratio of albumin), peritoneal thickness, neoangiogenesis and inflammatory reaction increased significantly (all P<0.05). Administration of heparin and LMWH markedly alleviated these above pathological changes. The protein and mRNA levels of HIF-1α, VEGF and TGF-β1 increased significantly in group GLU, and decreased significantly after administration of LMWH in a dose-dependent manner.


CONCLUSIONS
LMWH ameliorates peritoneal function and inhibits peritoneal fibrosis, possibly through suppression of HIF-1α, VEGF and TGF-β1.
Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Juan
J
Li
Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Zhi Yong
ZY
Guo
Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Xian Hua
XH
Gao
Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Qi
Q
Bian
Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Meng
M
Jia
Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Xue Li
XL
Lai
Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Tie Yun
TY
Wang
Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Xiao Lu
XL
Bian
Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Hai Yan
HY
Wang
D000818:Animals; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D005355:Fibrosis / Q000188:drug therapy; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology* / Q000627:therapeutic use; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D010537:Peritoneum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A