Heparanase Inhibitors May Reduce Risk of Diabetic Kidney Disease, Diabetic Retinopathy in Patients with Diabetes

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This agent can prevent the depletion of heparan sulphate in the endothelial glycocalyx layer of endothelial cells, ultimately protecting against vision loss and renal failure caused by diabetes.

A class of heparanase inhibitors called OVZ/HS-1638 may reduce microvascular complications associated with diabetes such as diabetic retinopathy (DR) and diabetic kidney disease (DKD), according to investigators who conducted an animal study on heparan sulphate (HS) inhibition with findings published in Cardiovascular Diabetology. Inhibiting heparanase can protect the endothelial glycocalyx (eGllx) that surrounds vascular endothelial cells, which can prevent endothelial dysfunction that leads to DR and DKD.

“[eGlx HS] plays a common mechanistic role in microvascular barrier function in the eye and kidney,” wrote authors in the paper. “Protecting the [eGlx] damage in diabetes…effectively prevents microvascular permeability changes associated with DR and DKD.”

More than 8% of individuals around the world have diabetes. The condition can worsen cardiovascular health, which can increase risk of microvascular barrier dysfunction, thus increasing the risk of microvascular diseases such as DR and DKD. DR leads to vision loss or vision impairment, and DKD is the primary cause of end stage renal failure.

Image credit: blackday | stock.adobe.com

Image credit: blackday | stock.adobe.com

The eGlx is a carbohydrate-rich layer on the surface of all vascular endothelial cells. It is comprised of proteoglycans and glycosaminoglycans, including HS. Notably, HS cleaving is a process that is upregulated in patients with diabetes. In effect, investigators hypothesized that preserving HS in eGlx cells can preserve microvascular function and prevent complications.

Investigators used 2 mouse models to evaluate the role of HS in eGlx cells and disease progression. The first model included mice treated with heparanase 3, and the second model knocked out Exotosin-1 (a part of HS polymerase) from endothelial cells. This HS depletion led to retinal solute flux and glomerular albumin permeability in both groups (albumin permeability is a marker of DKD).

“Our data provides clear evidence that depleting HS from the glomerular eGlx is sufficient to negatively impact glomerular barrier function,” authors wrote.

However, investigators also evaluated the effects of OVZ/HS-1638 on HS loss in mice with diabetes, where they discovered that mice had better eGlx measurements and fewer microvascular permeability changes associated with DKD and DR. This also indicates that HS can have a significant role in disease progression.

There are limitations to this study. Primarily, there was no cohort of lean non-diabetic mice treated with OVZ/HS-1638. In addition, this study cannot confirm whether OVZ/HS-1638 reduces heparanase activity in vivo. Mice with diabetes were treated early in the disease progression, so there is no proof that the drug will be effective for late-stage disease.

Investigators will continue to research OVZ/HS-1638 with the goal of propelling it to analysis in pre-clinical studies in humans with DKD and DR in clinical trials. It has competitive advantages such as stability and cheaper synthesis compared to other commercial inhibitors, which investigators will continue to explore.

“Using our novel heparanase inhibitor OVZ/HS-1638, we have now demonstrated that heparanase acts on the eGlx, as inhibiting heparanase protects the eGlx and prevents microvascular permeability changes,” wrote authors.


REFERENCE

Gamez M, Elhegni HE, Fawaz S, et al. Heparanase inhibition as a systemic approach to protect the endothelial glycocalyx and prevent microvascular complications in diabetes. Cardiovasc Diabetol. 23, 50 (2024). doi:10.1186/s12933-024-02133-1

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