PROTECTING the endothelial glycocalyx using a novel heparanase inhibitor prevents microvascular permeability changes in diabetic retinopathy and diabetic kidney disease, offering a new systemic therapeutic approach for diabetic complications.
Diabetes is a major global health concern, leading to widespread vascular complications that significantly impact patient outcomes. Diabetic retinopathy and diabetic kidney disease are both characterised by early microvascular permeability changes that, if left untreated, progress to vision loss and renal failure. While the heparan sulphate-cleaving enzyme heparanase has been implicated in diabetic microvascular complications, the common mechanism driving microvascular dysfunction across multiple vascular beds remains unclear. Identifying targeted interventions that protect vascular integrity in diabetes is therefore a key clinical priority.
To investigate the role of heparan sulphate in microvascular barrier function, researchers used two mouse models of heparan sulphate depletion—one by enzymatic removal and another by endothelial-specific genetic ablation of Ext1. Both models exhibited endothelial glycocalyx thinning, increased retinal solute flux, and greater glomerular albumin permeability, highlighting the importance of endothelial glycocalyx integrity in maintaining microvascular health. A Type 2 diabetic mouse model was then used to assess the therapeutic potential of OVZ/HS-1638, a novel heparanase inhibitor. Treatment with OVZ/HS-1638 preserved endothelial glycocalyx depth and effectively prevented the microvascular permeability changes associated with both diabetic retinopathy and diabetic kidney disease.
These findings demonstrate that the endothelial glycocalyx and its heparan sulphate component play a fundamental role in vascular barrier function in diabetes, influencing both ocular and renal microvascular health. By targeting heparanase activity, OVZ/HS-1638 offers a promising systemic approach to protecting against diabetes-related microvascular complications. Given the lack of effective therapies that address both diabetic retinopathy and diabetic kidney disease simultaneously, this study provides strong evidence for further clinical development of heparanase inhibitors.
Jenna Lorge, EMJ
Reference
Gamez M et al. Heparanase inhibition as a systemic approach to protect the endothelial glycocalyx and prevent microvascular complications in diabetes. Cardiovasc Diabetol. 2024;DOI:10.1186/s12933-024-02133-1.
