Nephroprotective Effect of Heparanase in Experimental Nephrotic Syndrome

<div><p>Background</p><p>Heparanase, an endoglycosidase that cleaves heparan sulfate (HS), is involved in various biologic processes. Recently, an association between heparanase and glomerular injury was suggested. The present study examines the involvement of heparanase in the pathogenesis of Adriamycin-induced nephrotic syndrome (ADR-NS) in a mouse model.</p><p>Methods</p><p>BALB/c wild-type (<i>wt</i>) mice and heparanase overexpressing transgenic mice (<i>hpa</i>-TG) were tail-vein injected with either Adriamycin (ADR, 10 mg/kg) or vehicle. Albuminuria was investigated at days 0, 7, and 14 thereafter. Mice were sacrificed at day 15, and kidneys were harvested for various analyses: structure and ultrastructure alterations, podocyte proteins expression, and heparanase enzymatic activity.</p><p>Results</p><p>ADR-injected <i>wt</i> mice developed severe albuminuria, while ADR-<i>hpa</i>-TG mice showed only a mild elevation in urinary albumin excretion. In parallel, light microscopy of stained cross sections of kidneys from ADR-injected <i>wt</i> mice, but not <i>hpa</i>-TG mice, showed mild to severe glomerular and tubular damage. Western blot and immunofluorescence analyses revealed significant reduction in nephrin and podocin protein expression in ADR-<i>wt</i> mice, but not in ADR-<i>hpa</i>-TG mice. These results were substantiated by electron-microscopy findings showing massive foot process effacement in injected ADR-<i>wt</i> mice, in contrast to largely preserved integrity of podocyte architecture in ADR-<i>hpa</i>-TG mice.</p><p>Conclusions</p><p>Our results suggest that heparanase may play a nephroprotective role in ADR-NS, most likely independently of HS degradation. Moreover, <i>hpa</i>-TG mice comprise an invaluable <i>in vivo</i> platform to investigate the interplay between heparanase and glomerular injury.</p>