Researchers have identified a novel inhibitor drug that, when given to mice, prevented both eye and kidney complications commonly seen in diabetics. With the potential for one medication to treat two complications, further research is being done to advance the drug to clinical trials.
Even when it’s well managed, diabetes can lead to complications that affect the body’s small blood vessels or microvasculature. Two of the most common microvascular complications are diabetic retinopathy (DR), the leading cause of vision loss and blindness in diabetics, and diabetic kidney disease (DKD), which can result in kidney failure.
Although there are treatments directed at the symptoms of DR and DKD, there is currently nothing to prevent these complications. But with the University of Bristol researchers leading a study identifying a drug that prevented both diabetic eye and kidney complications in mice, a preventive treatment might soon exist.
“Our findings are exciting as we have shown that one type of medication might be able to prevent different diabetic complications, which is a global health problem for adults living with diabetes,” said Rebecca Foster, senior author of the study.
Previous studies have suggested that DR and DKD have common mechanisms underlying their development and progression as both are caused by dysfunction of the microvasculature barrier, particularly the endothelial glycocalyx, a protective layer that lines the inner surface of all vascular endothelial cells and is a determinant of small blood vessel health.
The glycocalyx is made up of carbohydrates that include the heparan sulfate molecule. Heparan sulfate is synthesized into chains inside the cell that are moved to the cell’s surface, where they can be directly modified (cleaved) by the enzyme heparanase at ‘hot spots’ along the chain, affecting the glycocalyx’s barrier function. In diabetics, heparanase is systematically upregulated and elevated in the eye membranes of patients with DR and the kidneys of those with DKD.
The researchers used a unique heparanase inhibitor, OVZ/HS-1638, to therapeutically target the glycocalyx in type 2 diabetic mouse models. Starting with the eyes, they noticed that the depth of the retinal glycocalyx was reduced in the untreated mice, but it wasn’t in mice treated with OVZ/HS-1638. They tested the ‘leakiness’ of the glycocalyx by measuring extracellular albumin, finding that the amount of albumin in the retinal tissue of the treated mice was significantly lower.
Moving on to the kidneys, the researchers found that, as they’d observed with the eyes, glycocalyx depth in the glomerulus (the network of small vessels that filter the blood) was significantly reduced in untreated diabetic mice but not in those given the heparanase inhibitor. When they measured the urine albumin-creatinine ratio (uACR), which shows whether albumin has leaked into the urine through the glomerular vessels, untreated mice had a significantly higher uACR than inhibitor-treated mice.
The findings provide evidence that protecting the glycocalyx using a heparanase inhibitor was an effective systemic approach to protect against microvascular complications in diabetes. Further studies into the drug’s pharmacokinetics, bioavailability and safety are in progress to support its potential for clinical evaluation.
“We are currently conducting research to advance our novel class of inhibitors to clinical use,” said Monica Gamez, lead and corresponding author of the study.
The study was published in the journal Cardiovascular Diabetology.
Source: University of Bristol
