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 low–molecular 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.