Abstract
ObjectiveSulodexide 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.MethodsMale 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.ResultsMice 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.ConclusionsOur 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.
Highlights
Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in developed countries
We demonstrated that sulodexide improved proteinuria and renal function in mice with DN, which was associated with increased perlecan expression along the glomerular basement membrane (GBM)
A loss of heparan sulfate proteoglycans in the GBM contributes to proteinuria in glomerular diseases including DN [11,31] and quantitative and qualitative changes in the de novo synthesis of heparan sulfate proteoglycan core protein and/or sulfation pattern of the heparan sulfate glycosaminoglycan chains have been proposed as pathogenic mechanisms [27,32]
Summary
Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in developed countries. DN is characterized by glomerular hypertrophy, basement membrane thickening, disruption of the glomerular permeability barrier, progressive accumulation of glomerular matrix, culminating in glomerulosclerosis, tubulointerstitial fibrosis, and progressive proteinuria and deterioration of renal function [1,2,3,4]. The extracellular matrix (ECM) plays an active role in regulating the structure and function of adjacent cells, and influences cell morphology, differentiation, anchorage and intercellular communication [5,6]. Perlecan is a heparan sulfate proteoglycan that maintains normal glomerular basement membrane (GBM) structure [10,11], and is involved in the transport of cells and small molecules across the GBM. Perlecan is a major contributor to the perm-selectivity of the GBM and a reduction of these negatively charged macromolecules results in proteinuria [12]
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