RESUMO
Fibrosis is the end point of most renal diseases, and several glycosaminoglycans have been shown to attenuate this process. Marine invertebrate glycosaminoglycans with unique structures have opened the possibility to test these new compounds on renal fibrosis. The effect of a fucosylated chondroitin sulfate from an echinoderm marine species is reported with the use of a model of renal fibrosis in rats, termed unilateral ureteral obstruction. Animals were given 4 mg/kg body wt of fucosylated chondroitin sulfate intraperitoneally, once a day. After 14 days, their kidneys were examined by histological, immunohistochemical, and biochemical methods. Compared with control mice, collagen deposition decreased in the course of renal fibrosis in the animals receiving fucosylated chondroitin sulfate, as revealed by Sirius red staining and hydroxyproline content. The cellularity related to myofibroblasts and macrophages was also reduced, as was the production of transforming growth factor (TGF)-ß. The glycosaminoglycan content increased in the renal interstitium of animals submitted to unilateral ureteral obstruction compared with the control contralateral kidney, mostly due to an increase of chondroitin sulfate content. Interestingly, no change in the pattern of glycosaminoglycan deposition was observed after administration of fucosylated chondroitin sulfate. Fibrosis induced by unilateral ureteral obstruction is attenuated in P-selectin-deficient mice, which also do not respond to the invertebrate glycosaminoglycan. In conclusion, fucosylated chondroitin sulfate attenuates renal fibrosis on a ureteral obstruction model in mice preponderantly through a P-selectin-mediated mechanism.
Assuntos
Sulfatos de Condroitina/uso terapêutico , Selectina-P/fisiologia , Obstrução Ureteral/patologia , Animais , Colágeno/metabolismo , Fibrose/prevenção & controle , Rim/metabolismo , Rim/patologia , Macrófagos/metabolismo , Masculino , Camundongos , Miofibroblastos/metabolismo , Ratos , Fator de Crescimento Transformador beta/metabolismo , Obstrução Ureteral/metabolismoRESUMO
Chondroitin sulfate, a glycosaminoglycan that is widely distributed among mammals, is used as a therapeutic agent in various diseases. Here, we focus on its absorption, excretion and tissue accumulation in rats. The concentration of 35S-chondroitin sulfate (35S-CS) in plasma reaches a peak in the first 5 min after intravenous administration and simultaneously increases in the urine. Approximately 25% of the 35S found in the urine appears as inorganic sulfate, indicating that 35S-CS is partially degraded during its renal filtration. The glycosaminoglycan is retained mainly by the liver and the kidney, where the amount of 35S reaches a plateau in the first 30 min, remains constant up to 2 h and then decreases markedly. Renal filtration and organ accumulation of 35S-CS decreases as the size of the glycosaminoglycan is reduced, especially in the liver. A derivative of 35S-CS that resists hyaluronidase digestion due to reduction of its glucuronic acid carboxyl groups appears at lower concentrations in plasma and in urine when compared with native 35S-CS. This derivative reaches higher levels in the kidney but lower levels in the liver when compared with the native molecule. Overall, our results indicate a balance between renal and hepatic mechanisms for removing chondroitin sulfate from plasma. The renal filtration increases as the molecular weight of the glycosaminoglycan decreases, whereas hepatic removal requires structural integrity and the presence of high-molecular-weight chains.