Glycosaminoglycans prevent morphological renal alterations and albuminuria in diabetic rats

Abstract

Abnormal glycosaminoglycan metabolism is involved in the onset of anatomo-functional derangements in diabetic nephropathy, and determines the loss of glomerular basement membrane anionic charges leading to albuminuria. Glycosaminoglycan administration was shown to increase the negative electrical potential of the vessel wall, inhibit mesangial cell proliferation, which is an anatomical hallmark of diabetic nephropathy, and slow down the progression to uremia in subtotally nephrectomized rats, a model that shares some pathogenetic key events with diabetic nephropathy. Based on these considerations, we verified the effect of exogenous glycosaminoglycans on renal involvement in streptozotocin diabetic rats. Long-term administration of two glycosaminoglycans (low-molecular weight heparin and dermatan sulphate) prevented glomerular basement membrane thickening, glomerular anionic charge reduction, as well as the onset of albuminuria without affecting glomerular filtration rate and metabolic control of the disease. Our data demonstrate that the long-term administration of glycosaminoglycans has a favorable effect on morphological and functional renal abnormalities in diabetic rats.

Hyaluronan Structures Synthesized by Rat Mesangial Cells in Response to Hyperglycemia Induce Monocyte Adhesion

“…RMCs-Diabetic nephropathy in animal models is ameliorated when the animals are treated with heparin or heparan sulfate in vivo (32,33). Therefore, two different isolates of RMCs were passaged either 3 or 5 times in the presence or absence of 10 g/ml heparin.…”

Glycosaminoglycan therapy for long-term diabetic complications?

“…In view of these considerations, the effect of heparin and GAGs on diabetic nephropathy was studied in the streptozotocin diabetic model. This approach reduced glomerular basement membrane thickening [12] and anionic charge loss [12], as well as mesangial area expansion [15], and prevented the onset of albuminuria [12,16] and the disorder in charge permselectivity [16]. Marshall et al [15], however, were not able to confirm a reduction of albumin excretion in female streptozotocin diabetic Wistar rats on a twice daily dose of 200 units heparin over a period of 6 months.…”

“…The treatment of diabetic nephropathy with GAGs was originally proposed on the basis of the somewhat simple idea that restoring the lacking anionic charges and GAGs to the diabetic kidney could cure the albuminuria and putatively return the above described cell functional anomalies to normal [12] (Fig. 2).…”

“…In the streptozotocin model, heparin down-regulates collagen over-expression by interfering with the transforming growth factor (TGF)-b1 autocrine/paracrine loop, which is known to be activated in the diabetic kidney and is thought to play a very important role in the pathogenesis of this complication [9]. Low molecular weight dermatan sulphate, the GAG derivative that prevents the onset of diabetic renal alterations in the streptozotocin model [12], also inhibits protein-kinase-C-dependent activation of the TGF-b1 gene in mesangial cells in vitro [20].…”

“…Danaparoid, a mixture of sulphated GAGs composed mainly of HS, also lowered proteinuria in a small double-blind, crossover study in Type I diabetic patients with albumin excretion rates higher than 300 mg/24 h [23]. A formulation composed of the two GAGs that were active in preventing diabetic nephropathy in the experimental model [12] was also tested in patients. Indeed, sulodexide, a GAG formulation composed of 80 % fast-moving heparin and 20 % dermatan sulphate, was reported to reduce albuminuria in Type I and Type II diabetic patients [24,25], and this effect lasted several weeks after its withdrawal [26].…”