Sulodexide improves renal function through reduction of vascular endothelial growth factor in type 2 diabetic rats

Jin Joo Cha, Young Sun Kang, Young Youl Hyun, Sang Youb Han, Yi Hwa Jee, Kum Hyun Han, Jee Young Han, Dae-Ryong Cha

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Aims 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. Main methods Diabetic rats were treated with or without sulodexide at 10 mg/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. Key findings 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. Significance 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.

Original languageEnglish
Pages (from-to)1118-1124
Number of pages7
JournalLife Sciences
Volume92
Issue number23
DOIs
Publication statusPublished - 2013 Jun 21

Fingerprint

Vascular Endothelial Growth Factor A
Rats
Kidney
p38 Mitogen-Activated Protein Kinases
Podocytes
Inbred OLETF Rats
Diabetic Nephropathies
glucuronyl glucosamine glycan sulfate
Chemical activation
Rat control
Glomerular Basement Membrane
Drinking Water
Albumins
Tissue
Glucose
Molecules

Keywords

  • Diabetic nephropathy
  • Type 2 diabetes mellitus
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Sulodexide improves renal function through reduction of vascular endothelial growth factor in type 2 diabetic rats. / Cha, Jin Joo; Kang, Young Sun; Hyun, Young Youl; Han, Sang Youb; Jee, Yi Hwa; Han, Kum Hyun; Han, Jee Young; Cha, Dae-Ryong.

In: Life Sciences, Vol. 92, No. 23, 21.06.2013, p. 1118-1124.

Research output: Contribution to journalArticle

Cha, Jin Joo ; Kang, Young Sun ; Hyun, Young Youl ; Han, Sang Youb ; Jee, Yi Hwa ; Han, Kum Hyun ; Han, Jee Young ; Cha, Dae-Ryong. / Sulodexide improves renal function through reduction of vascular endothelial growth factor in type 2 diabetic rats. In: Life Sciences. 2013 ; Vol. 92, No. 23. pp. 1118-1124.
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T1 - Sulodexide improves renal function through reduction of vascular endothelial growth factor in type 2 diabetic rats

AU - Cha, Jin Joo

AU - Kang, Young Sun

AU - Hyun, Young Youl

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AU - Jee, Yi Hwa

AU - Han, Kum Hyun

AU - Han, Jee Young

AU - Cha, Dae-Ryong

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N2 - Aims 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. Main methods Diabetic rats were treated with or without sulodexide at 10 mg/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. Key findings 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. Significance 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.

AB - Aims 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. Main methods Diabetic rats were treated with or without sulodexide at 10 mg/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. Key findings 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. Significance 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.

KW - Diabetic nephropathy

KW - Type 2 diabetes mellitus

KW - Vascular endothelial growth factor

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