title: Sulodexide improves renal function through reduction of vascular endothelial growth factor in type 2 diabetic rats.
abstract: OBJECTIVE
  Sulodexide is a promising therapeutic drug for the management of diabetic nephropathy. Although sulodexide has demonstrated a renoprotective effect through its ability to restore glomerular ionic permselectivity, the exact mechanism is still not clear. We investigated the effects of long-term sulodexide treatment on diabetic nephropathy in Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats.
  
  
  METHODS
  Diabetic rats were treated with or without sulodexide at 10mg/kg/day in the drinking water for nine months. Renal morphology and changes in VEGF and p38 mitogen-activated protein kinase (p38 MAPK), urinary levels of albumin (UAE) and urinary VEGF excretion were determined. To define the direct effects of sulodexide, we performed an in vitro experiment using podocytes.
  
  
  RESULTS
  UAE was significantly higher in OLETF rats than in control LETO rats, and the sulodexide group showed significantly decreased UAE after six months of treatment. Interestingly, urinary VEGF levels were also significantly decreased in the sulodexide-treated group. In accordance with UAE and urinary VEGF changes, the renal expression of profibrotic molecules was significantly decreased after sulodexide treatment. In addition, the activation of p38 MAPK, assessed by measuring the level of phospho-specific p38 MAPK, increased in diabetic renal tissues and was markedly suppressed by sulodexide treatment. In cultured podocytes, sulodexide treatment significantly decreased high glucose-induced p38 MAPK activation and VEGF synthesis.
  
  
  CONCLUSIONS
  Sulodexide directly suppresses VEGF synthesis through the p38 MAPK pathway in podocytes, and these results suggest that sulodexide may provide renoprotection via suppression of renal VEGF synthesis independently of glomerular basement membrane ionic permselectivity in type 2 diabetic rats.
authors: Department of Internal Medicine, College of Medicine, Korea University, Republic of Korea.
authors: Jin Joo
authors: JJ
authors: Cha
authors: Young Sun
authors: YS
authors: Kang
authors: Young Youl
authors: YY
authors: Hyun
authors: Sang Youb
authors: SY
authors: Han
authors: Yi Hwa
authors: YH
authors: Jee
authors: Kum Hyun
authors: KH
authors: Han
authors: Jee Young
authors: JY
authors: Han
authors: Dae Ryong
authors: DR
authors: Cha
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D015153:Blotting, Western; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D006025:Glycosaminoglycans / Q000494:pharmacology* / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D020334:Rats, Inbred OLETF; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000502:physiology / Q000652:urine
chemical_list: D001786:Blood Glucose; D006025:Glycosaminoglycans; D007004:Hypoglycemic Agents; D042461:Vascular Endothelial Growth Factor A; C007858:glucuronyl glucosamine glycan sulfate