The Protective Role of Fucosylated Chondroitin Sulfate, a Distinct Glycosaminoglycan, in a Murine Model of Streptozotocin-Induced Diabetic NephropathyReport as inadecuate




The Protective Role of Fucosylated Chondroitin Sulfate, a Distinct Glycosaminoglycan, in a Murine Model of Streptozotocin-Induced Diabetic Nephropathy - Download this document for free, or read online. Document in PDF available to download.

Background

Heparanase-1 activation, albuminuria, and a decrease in glomerular heparan sulfate HS have been described in diabetic nephropathy DN. Glycosaminoglycan GAG-based drugs have been shown to have renoprotective effects in this setting, although recent trials have questioned their clinical effectiveness. Here, we describe the effects of fucosylated chondroitin sulfate FCS, a novel GAG extracted from a marine echinoderm, in experimentally induced DN compared to a widely used GAG, enoxaparin ENX.

Methods

Diabetes mellitus DM was induced by streptozotocin in male Wistar rats divided into three groups: DM without treatment, FCS 8 mg-kg, and ENX 4 mg-kg, administered subcutaneously. After 12 weeks, we measured blood glucose, blood pressure, albuminuria, and renal function. The kidneys were evaluated for mesangial expansion and collagen content. Immunohistochemical quantifications of macrophages, TGF-β, nestin and immunofluorescence analysis of heparanase-1 and glomerular basement membrane GBM HS content was also performed. Gene expression of proteoglycan core proteins and enzymes involved in GAG assembly-degradation were analyzed by TaqMan real-time PCR.

Results

Treatment with GAGs prevented albuminuria and did not affect the glucose level or other functional aspects. The DM group exhibited increased mesangial matrix deposition and tubulointerstitial expansion, and prevention was observed in both GAG groups. TGF-β expression and macrophage infiltration were prevented by the GAG treatments, and podocyte damage was halted. The diabetic milieu resulted in the down-regulation of agrin, perlecan and collagen XVIII mRNAs, along with the expression of enzymes involved in GAG biosynthesis. Treatment with FCS and ENX positively modulated such changes. Heparanase-1 expression was significantly reduced after GAG treatment without affecting the GBM HS content, which was uniformly reduced in all of the diabetic animals.

Conclusions

Our results demonstrate that the administration of FCS prevented several pathological features of ND in rats. This finding should stimulate further research on GAG treatment for this complication of diabetes.



Author: Conrado L. R. Gomes, Cristina L. Leão, Carolina Venturotti, André L. Barreira, Gabriela Guimarães, Roberto J. C. Fonseca, Rodr

Source: http://plos.srce.hr/



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