Sulodexide decreases albuminuria and regulates matrix protein accumulation in C57BL/6 mice with streptozotocin-induced type I diabetic nephropathy

PLoS One. 2013;8(1):e54501. doi: 10.1371/journal.pone.0054501. Epub 2013 Jan 22.

Abstract

Objective: Sulodexide is a mixture of glycosaminoglycans that may reduce proteinuria in diabetic nephropathy (DN), but its mechanism of action and effect on renal histology is not known. We investigated the effect of sulodexide on disease manifestations in a murine model of type I DN.

Methods: Male C57BL/6 mice were rendered diabetic with streptozotocin. After the onset of proteinuria, mice were randomized to receive sulodexide (1 mg/kg/day) or saline for up to 12 weeks and renal function, histology and fibrosis were examined. The effect of sulodexide on fibrogenesis in murine mesangial cells (MMC) was also investigated.

Results: Mice with DN showed progressive albuminuria and renal deterioration over time, accompanied by mesangial expansion, PKC and ERK activation, increased renal expression of TGF-β1, fibronectin and collagen type I, III and IV, but decreased glomerular perlecan expression. Sulodexide treatment significantly reduced albuminuria, improved renal function, increased glomerular perlecan expression and reduced collagen type I and IV expression and ERK activation. Intra-glomerular PKC-α activation was not affected by sulodexide treatment whereas glomerular expression of fibronectin and collagen type III was increased. MMC stimulated with 30 mM D-glucose showed increased PKC and ERK mediated fibronectin and collagen type III synthesis. Sulodexide alone significantly increased fibronectin and collagen type III synthesis in a dose-dependent manner in MMC and this increase was further enhanced in the presence of 30 mM D-glucose. Sulodexide showed a dose-dependent inhibition of 30 mM D-glucose-induced PKC-βII and ERK phosphorylation, but had no effect on PKC-α or PKC-βI phosphorylation.

Conclusions: Our data demonstrated that while sulodexide treatment reduced proteinuria and improved renal function, it had differential effects on signaling pathways and matrix protein synthesis in the kidney of C57BL/6 mice with DN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / complications
  • Albuminuria / drug therapy
  • Albuminuria / pathology
  • Animals
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / pathology
  • Diabetic Nephropathies / complications
  • Diabetic Nephropathies / drug therapy*
  • Diabetic Nephropathies / pathology
  • Gene Expression Regulation / drug effects
  • Glucose / administration & dosage
  • Glucose / metabolism
  • Glycosaminoglycans / administration & dosage*
  • Humans
  • Male
  • Mesangial Cells / drug effects
  • Mesangial Cells / metabolism
  • Mesangial Cells / pathology
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation / drug effects
  • Signal Transduction / drug effects

Substances

  • Glycosaminoglycans
  • glucuronyl glucosamine glycan sulfate
  • Glucose

Grants and funding

This study was supported by the Hong Kong Research Grant Council General Research Fund (HKU 7653/06 M), UGC Matching Grant Scheme (Phase III, 20730358 and Phase IV, 20740425) and the Estate of the late Mr Chan Wing Hei. S. Yung is supported by funding from the Yu Chiu Kwong Endowed Professorship in Medicine and the Wai Hung Charitable Foundation Limited awarded to T. M. Chan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.