The Effect And Mechanism Of Low Molecular Weight Fucoidan From Saccharina Japonica On Diabetic Nephropathy

Diabetic nephropathy(DN) is a serious and major microvascular complication caused by diabetes, it can lead to chronic renal failure and end-stage renal failure, and it is the major cause of death in diabetic patient. DN is a kind of metabolic disorders caused by diabetes, its onset and development are involved in various pathological processes. It is extremely urgent to look for an effective drug for DN and improve patient quality of life.Low molecular weight fucoidan(LMWF) is a highly sulfated heteropolysaccharide degraded from fucoidan of Saccharina japonica, it is made up mostly of fucose and galactose. LMWF has a variety of activities on anticoagulant, anti-inflammatory, antiangiogenic, antioxidant, antitumor and antiviral and so on. Polysaccharide and glycoconjugates are important biomacromolecule, they play a key role in the onset and development of DN. LMWF in one of natural sulfated polysaccharides from seaweed, it may affect the function of glycoconjugates which are involved in the onset and development of DN, and inhibit the development of DN. This research aims to explore the mechanism and treatment of LMWF on streptozotocin(STZ)-induced DN model. The main results are as follows:(1) STZ were used to induce DN model in rats, and then DN rats had typical DN symptoms, the levels of microscale-total protein(M-TP) and urinary albumin(u Alb) were increased obviously. LMWF could prevent body weight losing and reduction of urine by oral administration, significantly reduced the levels of biochemical indices in blood and urine. LMWF decreased M-TP and u Alb content in urine, then reduced the incidence of proteinuria. In addition, LMWF mitigated the renal damage of DN rats, maintained the basic structure and function of glomerulus, and then alleviated the onset and development of DN.(2) It is understood that inflammation is associated with the onset and process of DN. The hematoxylin and eosin(HE) stained sections exhibited LMWF protected normal morphological structures and reduced inflammatory cell infiltration in the kidneys of DN rats. Furthermore, LMWF significantly decreased the levels of P-selectin and selectin-dependent inflammatory cytokines at both transcriptional and protein levels. Thus, our results found that LMWF alleviated inflammation through the modulation of P-selectin and inflammatory cytokines and protected the renal function in DN rats.(3) Glomerular basement membrane(GBM) is the necessary component of glomerular filtration function, and HSPGs are the important composition of GBM. Heparanase(HPSE) can cleave the heparan sulfate(HS) chain of HSPGs, lead to the physiological structure and function of glomerulus damaged. Results showed that LMWF could lower hyaluronic acid(HA) levels and advanced glycosylation end product-specific receptor(AGER) levels in DN rats. And LMWF maintained the structural integrity of GBM and glomerulus, improved the glomerular filtration function, protected glycosaminoglycan from abnormal degrading, prevented advanced glycosylation end product(AGE) from being generated and accumulating. Furthermore, LMWF could downregulate the levels of HPSE and growth factors at both the transcriptional and protein levels. Thus, our results found that LMWF inhibited the positive expression of HPSE and growth factors, maintained the normal structure and function of glomerulus, then ameliorated the development of DN.