title: The protective role of fucosylated chondroitin sulfate, a distinct glycosaminoglycan, in a murine model of streptozotocin-induced diabetic nephropathy.
abstract: 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.
authors.affiliation: Serviço e Disciplina de Nefrologia, Departamento de Clínica Médica and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Conrado L R
authors.initials: CL
authors.lastname: Gomes
authors.affiliation: Serviço e Disciplina de Nefrologia, Departamento de Clínica Médica and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Cristina L
authors.initials: CL
authors.lastname: Leão
authors.affiliation: Serviço e Disciplina de Nefrologia, Departamento de Clínica Médica and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Carolina
authors.initials: C
authors.lastname: Venturotti
authors.affiliation: Serviço e Disciplina de Nefrologia, Departamento de Clínica Médica and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: André L
authors.initials: AL
authors.lastname: Barreira
authors.affiliation: Serviço e Disciplina de Nefrologia, Departamento de Clínica Médica and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Guimarães
authors.affiliation: Laboratório de Tecido Conjuntivo, Instituto de Bioquímica Médica and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Roberto J C
authors.initials: RJ
authors.lastname: Fonseca
authors.affiliation: Laboratório de Radiobiologia Molecular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Rodrigo S
authors.initials: RS
authors.lastname: Fortunato
authors.affiliation: Laboratório de Tecido Conjuntivo, Instituto de Bioquímica Médica and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Paulo A S
authors.initials: PA
authors.lastname: Mourão
authors.affiliation: Serviço e Disciplina de Nefrologia, Departamento de Clínica Médica and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Alvimar G
authors.initials: AG
authors.lastname: Delgado
authors.affiliation: Serviço e Disciplina de Nefrologia, Departamento de Clínica Médica and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Takiya
authors.affiliation: Serviço e Disciplina de Nefrologia, Departamento de Clínica Médica and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Maurilo
authors.initials: M
authors.lastname: Leite
mesh_terms: D000419:Albuminuria / Q000378:metabolism; D000818:Animals; D002809:Chondroitin Sulfates / Q000494:pharmacology* / Q000627:therapeutic use*; D003094:Collagen / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006025:Glycosaminoglycans / Q000494:pharmacology / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin
chemical_list: D006025:Glycosaminoglycans; C517150:fucosylated chondroitin sulfate; D013311:Streptozocin; D002809:Chondroitin Sulfates; D003094:Collagen