Abnormal Glomerular Permeability Characteristics in Diabetic Nephropathy

Abstract

The physicochemical characteristics of the glomerular capillary filtration membrane restrict the passage of macromolecules on the basis of molecular weight, charge, and shape. The proposed ionic charge permselectivity characteristics of the glomerular basement membrane (GBM) are determined by its chemical composition, primarily the highly sulfated glycosaminoglycan heparan. In diabetic nephropathy, the heparan sulfate content of the GBM is diminished. It has been proposed that decreased GBM heparan sulfate content causes decreased permselectivity to negatively charged macromolecules such as albumin, allowing this protein to leak into the urinary space. One possible explanation for decreased GBM heparan sulfate content in diabetic nephropathy is the observation that heparanase, an enzyme capable of degrading heparan sulfate, is upregulated in the glomerular epithelial cell (GEC) in response to increased glucose. Increased GEC heparanase activity has been demonstrated in glomeruli in diabetic kidneys, and increased urine heparanase has been observed in diabetic nephropathy. In vitro studies have shown that GEC heparanase activity depends on the glucose concentration of the culture medium. GEC heparanase activity can be inhibited by heparin compounds. Sulodexide, an orally active lowmolecular weight heparin, has been shown to lower urine albumin excretion. The working hypothesis that has emerged is that sulodexide may be an in vivo heparanase inhibitor that reaches the glomerular capillary wall and prevents heparan sulfate degradation, thus allowing reconstruction of heparan sulfate content and restoration of GBM ionic permselectivity. Two clinical trials are currently being carried out to determine whether sulodexide is renoprotective in diabetic nephropathy. Diabetes Care 31 (Suppl. 2):S202-S207, 2008

The Role of Heparanase in Diseases of the Glomeruli

“…Unfortunately, these substances are very rapidly inactivated, more rapidly than unfractioned heparin (Naggi et al 2005). The latest observations with sulodexide (an oral low-molecularweight heparin-like compound) indicate that the hindrance of its short action duration can be successfully overcome (Lewis and Xu 2008). PI-88 (phosphomannopentaose sulfate), a mixture of sulfated synthetic oligosaccharides, is the more promising of the drugs mentioned above.…”

Old and new applications of non-anticoagulant heparin

“…Tested from 1967 in severe malaria clinical trials, after some overall promising outcomes, were discontinued due to severe intracranial bleeding [44] 4:1 weight ratio [26]. Clinical trials of parental LMHWs and oral sulodexide in diabetic nephropathic patients were also reported and their beneficial effects correlated principally with their inhibition of heparanase and oxidative renal insult [71]. In the early 1990s, clinical trials showed that "Ateroid" (present in the Italian market until 2014 as oral and parental formulations), a mixture of glycosaminoglycans (GAGs) similar to Sulodexide, may have improved the cognitive function of patients with various degenerative conditions correlated to amyloid diseases, such as Alzheimer's (AD), Parkinson's (PD) diseases and transmissible spongiform encephalopathy (TSE) [60].…”

Urinary biomarkers of diabetic nephropathy

“…The etiology is multifaceted and caused by the altered composition of the glomerular basement membrane, impairing both size and charge selectivity, 26 podocyte dysfunction, and more. 26,27 We present a number of biomarkers that are derived from this derangement, with a special focus on podocyte markers later on. Cystatin C is a cysteine proteinase inhibitor which is produced by all nucleated cells at a constant rate.…”