Mode of action and therapeutic implications (PPT / 2216.5 KB)

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Heparanase in diabetic
nephropathy: Mode of action and
therapeutic implications
Dr. Tzahi Neuman
Cloning the Heparanase
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
Heparan-sulfate (HS) glycosaminoglycans
at the cell surface and in the ECM
•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.
Adapted from Sasisekharan et al., Nature Reviews Cancer 2002
Heparanase Activity
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).
Processing and activation of proheparanase by Cathepsin L
Pro-Hpa 65 kDa
Cathepsin L
Cathepsin L inhibitor
65 kDa
65 kDa
50 kDa
Processing
8 kDa
50 kDa
8 kDa
+
-
+
+
-
+
+
+
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
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