Finding raises hopes for drug to reverse diabetes complications

Dr Phil Kantharidis, heads a
research group working on
diabetic complications

by Anne Crawford

Curiosity, lateral thinking, a visiting post-doctoral researcher in the right place at the right time and some scientific detective work have led to a finding that has researchers in the Department of Diabetes excited.

The lethal-7 (let-7) family of small molecules is well known for the role it plays in modulating inflammatory responses, its members linked to many different diseases including cancer, liver and lung fibrosis and cardiovascular disease.

After previous work that identified a role for let-7 micro RNAs (miRNA) in kidney disease, Department of Diabetes Senior Research Fellow Dr Phillip Kantharidis wondered if let-7 played a role in diabetes complications.


“About a third of people with diabetes suffer ill-health because of complications, which usually affect their kidneys, heart, cardiovascular health, retinopathy and neuropathy,” Dr Kantharidis said. “The consequences can be quite severe.

“We had no idea if let-7 would play a role or not but it had gripped our interest,” he said.

Post-doctoral researcher Dr Eoin Brennan had just arrived from University College Dublin, Ireland, at the time that Dr Kantharidis was contemplating a study investigating let-7 and diabetes-associated atherosclerosis; Dr Brennan had coincidentally conducted previous research on let-7.

Atherosclerosis occurs due to the build-up of plaque inside the arteries, hardening and narrowing them. The plaque is a result of activation of vascular smooth muscle cells and endothelial cells, and immune cell recruitment to the site of inflammation.

In a study published in May in ‘Diabetes’, the researchers observed that let-7 levels were decreased in an animal model of diabetes-associated atherosclerosis and that this was promoting the vascular inflammation. Moreover, their study found that when let-7 levels were restored, tissue was protected from the effects of diabetes.

Let-7 could become a new target for anti-inflammatory therapy in diabetic vascular disease, it concluded.

Dr Brennan tested a drug – lipoxin A4 – that used naturally occurring molecules in the body to restore levels of let-7 in tissue.

“This is the first study looking at the role of let-7 in atherosclerosis – how it works, why it protects and how it decreases,” Dr Kantharidis said. “We also found the mechanisms by which we think let-7 decreases in atherosclerosis.”

Working backwards, the investigators identified several growth factors that were negatively regulating let-7. “Lipoxin A4 may be a master regulator of all these.”

The researchers are now further investigating the ability of lipoxin A4 to dampen down the inflammatory responses involved in atherosclerosis and to potentially reverse the disease.

“Our hope is to eventually be able to help patients who already have diabetic complications and to reverse those complications, restoring health to the patients. It’s looking like both let-7 and lipoxin drugs will do that,” Dr Kantharidis said.

References

Brennan E, Wang B, McClelland A, Mohan M, Marai M, Beuscart O, Derouiche S, Gray S, Pickering R, Tikellis C, de Gaetano M, Barry M, Belton O, Ali-Shah ST, Guiry P, Jandeleit-Dahm KA, Cooper ME, Godson C, Kantharidis P. Protective Effect of Let-7 miRNA Family in Regulating Inflammation in Diabetes-Associated Atherosclerosis. Diabetes. 2017 May 9. pii: db161405. doi: 10.2337/db16-1405. [Epub ahead of print]

Wang B, Jha JC, Hagiwara S, McClelland AD, Jandeleit-Dahm K, Thomas MC, Cooper ME, Kantharidis P. Transforming growth factor-β1-mediated renal fibrosis is dependent on the regulation of transforming growth factor receptor 1 expression by let-7b. Kidney Int. 2014 Feb;85(2):352-61. doi: 10.1038/ki.2013.372. Epub 2013 Oct 2.