Nephroprotective Effect of Heparanase in Experimental Nephrotic Syndrome

Abstract

BackgroundHeparanase, 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.MethodsBALB/c wild-type (wt) mice and heparanase overexpressing transgenic mice (hpa-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.ResultsADR-injected wt mice developed severe albuminuria, while ADR-hpa-TG mice showed only a mild elevation in urinary albumin excretion. In parallel, light microscopy of stained cross sections of kidneys from ADR-injected wt mice, but not hpa-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-wt mice, but not in ADR-hpa-TG mice. These results were substantiated by electron-microscopy findings showing massive foot process effacement in injected ADR-wt mice, in contrast to largely preserved integrity of podocyte architecture in ADR-hpa-TG mice.ConclusionsOur results suggest that heparanase may play a nephroprotective role in ADR-NS, most likely independently of HS degradation. Moreover, hpa-TG mice comprise an invaluable in vivo platform to investigate the interplay between heparanase and glomerular injury.

Vitamin D attenuates proteinuria by inhibition of heparanase expression in the podocyte

“…Results in the paper by Assady et al [33] seem to be in contrast to previous studies that showed a pathological role of heparanase in models for diabetic nephropathy, minimal change disease, accelerated anti-GBM disease, and membranous glomerulopathy [2,3,7-9]. Unfortunately, their study [33] does not provide a mechanism for the observed nephroprotective effect of heparanase overexpression. However, it is possible that overexpression since birth makes the transgenic mice more resistant to AN development.…”

“…We previously showed that transgenic overexpression of heparanase did not result in proteinuria, which we explained by the lack of induced pathology [34]. Results in the paper by Assady et al [33] seem to be in contrast to previous studies that showed a pathological role of heparanase in models for diabetic nephropathy, minimal change disease, accelerated anti-GBM disease, and membranous glomerulopathy [2,3,7-9]. Unfortunately, their study [33] does not provide a mechanism for the observed nephroprotective effect of heparanase overexpression.…”

Heparanase Inhibition Reduces Glucose Levels, Blood Pressure, and Oxidative Stress in Apolipoprotein E Knockout Mice

“…Heparan sulphate has the ability to bind variable matrix proteins, collagen, laminin, and fibronectin, and plays an important role in cellular-extracellular matrix interactions [ 14 – 16 ]. As an important protein binder, heparan sulphate has important roles both in normal biologic processes, like cell differentiation [ 17 , 18 ], tissue repair [ 19 , 20 ], cell adhesion [ 21 ], cell migration, and tissue forming in the fetus [ 22 ], and in pathologic processes, like tumor formation and metastatic spread [ 17 , 18 , 23 – 25 ], angiogenesis in malignant tumors [ 26 , 27 ], autoimmune processes and inflammatory reactions [ 28 – 30 ], diabetes [ 31 ], kidney dysfunction [ 32 , 33 ], and vessel wall pathologies: thrombosis and atherosclerosis [ 34 – 36 ]. The bidirectional interaction between HSPGs and the ECM is important for keeping the continuity and integrity of tissues and organs.…”

Heparanase Overexpression Induces Glucagon Resistance and Protects Animals From Chemically Induced Diabetes

“…In contrast to these observations, heparanase has also been shown to have beneficial effects in some diseases. For instance, overexpression of this protein is protective against adriamycin-induced kidney injury (14). In the brain, fragmentation of HS because of heparanase cleavage reduced amyloid deposition in Alzheimer's disease (15).…”