ABSTRACT
It is well established that arterial glycosaminoglycans (GAG) undergo compositional and structural modifications during the development of atherosclerosis. On the other hand, metabolic acidosis is a common feature of chronic renal patients known to present accelerated atherogenesis. The present study was performed to determine the influence of acidosis in the modifications of aortic GAG in a model of atherosclerosis in rabbits. For this purpose, four groups of rabbits were kept for 8 weeks on a regimen of normal, hypercholesterolemic, acidemic and hypercholesterolemic plus acidemic diets. No difference was detected in the total GAG concentration among animals fed with normal, hypercholesterolemic and acidemic diets. However, we observed an increase in total GAG content when acidosis was associated with hypercholesterolemia. This increase was more pronounced in the thoracic aortic segment. The interaction between LDL and the aortic GAG was evaluated by formation of insoluble complexes. The results showed that GAG extracted from hypercholesterolemic rabbits exhibited a lower ability to interact with LDL, when compared to those fed normal diet. On the other hand, GAG extracted from rabbits submitted to hypercholesterolemic plus acidemic diet, did not show this behavior. In addition, the molecular weight of GAG from hypercholesterolemic animals, is lower than those from animals fed normal diet. Surprisingly, acidosis associated with hypercholesterolemia did not exhibit this alteration, keeping the molecular weight close to the normal range. In view of these results, we hypothesize that acidosis itself does not affect either the GAG composition or its interaction with LDL, however in an atherogenic condition, as can be seen in renal failure individuals, it may alter the GAG concentration and the size of the glycan chains.
Subject(s)
Acidosis, Lactic/physiopathology , Aorta, Thoracic/metabolism , Atherosclerosis/physiopathology , Cholesterol, LDL/metabolism , Glycosaminoglycans/metabolism , Animals , Aorta, Thoracic/pathology , Cholesterol, LDL/analysis , Cholesterol, LDL/blood , Disease Models, Animal , Male , RabbitsABSTRACT
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.
