The Role of Heparanase in Diseases of the Glomeruli

Abstract

The glomerular basement membrane (GBM) is a kind of net that remains in a state of dynamic equilibrium. Heparan sulfate proteoglycans (HSPGs) are among its most important components. There are much data indicating the significance of these proteoglycans in protecting proteins such as albumins from penetrating to the urine, although some new data indicate that loss of proteoglycans does not always lead to proteinuria. Heparanase is an enzyme which cleaves beta 1,4 D: -glucuronic bonds in sugar groups of HSPGs. Thus it is supposed that heparanase may have an important role in the pathogenesis of proteinuria. Increased heparanase expression and activity in the course of many glomerular diseases was observed. The most widely documented is the significance of heparanase in the pathogenesis of diabetic nephropathy. Moreover, heparanase acts as a signaling molecule and may influence the concentrations of active growth factors in the GBM. It is being investigated whether heparanase inhibition may cause decreased proteinuria. The heparanase inhibitor PI-88 (phosphomannopentaose sulfate) was effective as an antiproteinuric drug in an experimental model of membranous nephropathy. Nevertheless, this drug is burdened by some toxicity, so further investigations should be considered.

Role of Heparanase-Driven Inflammatory Cascade in Pathogenesis of Diabetic Nephropathy

“…Although other heparanase-related factors (i.e., HS degradation in the GBM, altered interactions between glomerular cells and GBM, or release of HS-bound bioactive molecules) (16,17) may also contribute to DN development, our recent observations unravel what we believe to be a previously unrecognized combinatorial circuit of heparanasedependent molecular events powering chronic inflammation and kidney injury in individuals with DN (Fig. 5).…”

“…While both causal involvement of heparanase in DN and the molecular mechanism underlying heparanase induction by hyperglycemic conditions/diabetic mediators were previously described by the present authors and others (11)(12)(13), the exact mode of heparanase action in DN pathogenesis has not been fully elucidated. Apart from heparanase-mediated loss of HS in the GBM, it was suggested that heparanase contributes to the development of DN by inducing changes in glomerular cell-GBM interactions due to the loss of HS; through the release of HS-bound growth factors, cytokines, and bioactive HS fragments in glomeruli; or by activating signaling cascades that alter cell properties and lead to proteinuria (16,17).…”

“…5A and B). Of note, heparanase expression is not limited solely to glomeruli, and was reported in the tubulointerstitial compartment as well (for review, see Szymczak et al [16]). The resulting latent 65-kDa proheparanase is then processed into its enzymatically active (8-plus 50-kDa) form by CatL, which is supplied by tubular cells activated by DM components (Fig.…”

“…For more than 2 decades, the HS contribution to GBM perm-selective filtration and the loss of HS in the GBM were linked to the pathophysiology of DN. More recently, several reports (16,17) challenged the notion that heparanase-mediated loss of HS in the GBM interferes with GBM barrier properties and represents the primary mechanism implicating the enzyme in DN. In parallel, the view on DN as a consequence of solely metabolic/hemodynamic alterations has been transformed in recent years, with clear evidence indicating that the activation of innate immunity and chronic inflammation plays a significant role in the pathogenesis of both diabetes and its complications, including DN (18,19).…”

Pentoxifylline Attenuates Proteinuria in Anti-Thy1 Glomerulonephritis via Downregulation of Nuclear Factor-κB and Smad2/3 Signaling

“…However, it should be pointed out that the reversal of downregulated nephrin and podocin mRNA/protein by PTX was not complete, which likely accounted for residual proteinuria and nephrinuria despite treatment. In addition, alterations in other elements of the glomerular filtration barrier, such as the endothelial syndecan-4 and glypican-1, and the glycosaminoglycan degrading hyaluronidase and heparanase, have been shown to participate in the development of proteinuria (5,(44)(45)(46). Because transcriptional regulation of these genes was not likely TNF-α-or TGF-β-dependent (47,48), PTX might not be able to modulate the dysregulated mRNA expression as seen in the present model.…”