Heparanase in diabetic nephropathy: Mode of action and

therapeutic implications

Dr. Tzahi Neuman

Vlodavsky et al. Nat Med. 1999 Jul;5(7):793-802.

Hulett MD, Parish CR. Nat Med. 1999 Jul;5(7):803-9.

Kussie et al. Biochem Biophys Res Commun. 1999 Jul 22;261(1):183-7.

Toyoshima M, Nakajima M. J Biol Chem. 1999 Aug 20;274(34):24153-60

Cloning the Heparanase

Heparan-sulfate (HS) glycosaminoglycans at the cell surface and in the ECM

Adapted from Sasisekharan et al., Nature Reviews Cancer 2002

•HS is a key element in the self-assembly, and barrier properties of the ECM (particularly, BM).

•HS is responsible for sequestration of the heparin-binding growth factors (i.e., bFGF, VEGF, KGF) in the ECM.

1.Enables cell movement through extracellular barriers during the processes involving cell migration (i.e., tumor invasion, implantation, extravasation of blood borne cells, etc).

2.Releases heparan sulfate-bound GF from ECM depots, making them available for growth factor-dependent processes (i.e., tumor growth, neovascularization, wound healing).

Heparanase Activity

65 kDa50 kDa

+ + + - + + - - +

8 kDa

Processing and activation of pro-heparanase by Cathepsin L

Pro-Hpa 65 kDa Cathepsin LCathepsin L inhibitor

65 kDa

8 kDa 50 kDa

Processing

The role of heparanase in Diabetic Nephropathy using

the STZ model

Changes in heparanase expression, HS content, and albuminuria in WT&KO mice in response to

STZ-induced diabetes.

Histopathologic changes in the kidneys of WT&KO mice in response to STZ-induced

diabetes.

Effect of heparanase inhibitor on albuminuria and renal damage in diabetic mice.

Effect of Heparanase inhibitor on albuminuria and TGFb expression

Summary

1.Heparanase is a predominant mammalian enzyme that cleaves heparan sulfate

2. Heparanase is overexpressed in the diabetic kidney

3.There is essential involvement of heparanase in the pathogenesis of DN.

4.Deletion of the heparanase gene protects diabetic mice from diabetic nephropathy (DN).

5.Heparanase inhibitor decreases the extent of albuminuria.

Summary (continue)

1.Heparanase enhances macrophage and thus increases the kidney-damaging properties of macrophages.

2.This findings will help in developing effective strategies to disrupt the heparanase-driven sequence of events in diabetic kidney disease, and in designing novel therapeutic interventions in DN