Effects of low molecular weight heparin in obstructed kidneys: decrease of collagen, fibronectin and TGF-beta, and increase of chondroitin/dermatan sulfate proteoglycans and macrophage infiltration.
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 growth 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.
Pecly
Inah M D
IM
Laboratório de Tecido Conjuntivo, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Brazil.
Gonçalves
Rômulo G
RG
Rangel
Ednei P
EP
Takiya
Christina M
CM
Taboada
Fernanda S
FS
Martinusso
Cesônia A
CA
Pavão
Mauro S G
MS
Leite
Maurilo
M
D000818:Animals; D015415:Biomarkers / Q000032:analysis*; D001707:Biopsy, Needle; D002465:Cell Movement / Q000187:drug effects; D002807:Chondroitin / Q000378:metabolism; D011508:Chondroitin Sulfate Proteoglycans / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D003871:Dermatan Sulfate / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D005353:Fibronectins / Q000187:drug effects / Q000378:metabolism; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology*; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008297:Male; D011336:Probability; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D012680:Sensitivity and Specificity; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation; D014517:Ureteral Obstruction / Q000188:drug therapy* / Q000473:pathology
D015415:Biomarkers; D011508:Chondroitin Sulfate Proteoglycans; D005353:Fibronectins; D006495:Heparin, Low-Molecular-Weight; D016212:Transforming Growth Factor beta; C032649:dermatan sulfate proteoglycan; D003871:Dermatan Sulfate; D002807:Chondroitin; D003094:Collagen