The streptozotocin rat model of diabetes
With an estimated 450 million diabetes patients worldwide in 2020, Diabetes mellitus has reached a pandemic proportion and represents a major unmet medical need. Various organs and tissues are damaged by prolonged exposure to high blood sugar levels, which leads to diabetes‐related complications such as cardiovascular disease, nephropathy, neuropathy, retinopathy and lower extremity amputation. These complications impact the quality of life of patients with diabetes and have become economic and healthcare burdens in many countries.
A common complication in diabetes is endothelial dysfunction, an impairment of endothelium-dependent vasorelaxation that makes diabetics vulnerable to end-organ damage and limb infections. TRPV4 is a member of the transient receptor potential (TRP) ion channel family known to make important contributions to vascular tone. The expression of TRPV4 has been shown by various pharmacological studies to be a functional component of endothelial cells in dilating rat aortic rings and carotid artery, mesenteric arteries and aortic myocytes. Studies have also provided evidence that suggest that one of the contributors to the vascular dysfunction in diabetes is a dysfunction in TRPV4. Another important integral membrane protein is Caveolin-1, it is the principal component of caveolae in membranes and is involved in multiple cellular functions such as endocytosis, cholesterol homeostasis, signal transduction, and mechanoprotection. Previous studies demonstrated that CAV1 is critical for insulin receptor-mediated signaling, insulin secretion, and potentially the development of insulin resistance.
Another important signaling molecule that play an essential role in maintaining vascular function is nitric oxide which is produced by endothelial cells through the endothelial nitric oxide synthase (eNOS) and plays a major role for many of these endothelial functions and indeed decreased NO production and bioavailability largely contribute to endothelial dysfunction in diabetes
There is compelling evidence that endothelial dysfunction serves as a key event in the development and progression of diabetic vascular complications. To look at these important signaling proteins in diabetes, a new published research paper in the European Journal of Pharmacology, Researchers from the University of Hertfordshire in the United Kingdom: Dr. Yousif Shamsaldeen, Dr. Lisa Lione and Dr. Christopher Benham investigated the association between reduced expression of TRPV4, eNOS and caveolin-1 and type 1 diabetic endothelial dysfunction. They showed that a reduced expression of TRPV4, eNOS and caveolin-1 was indeed associated with endothelial dysfunction in diabetic disease model in rats.
They used a well-accepted animal disease model to study diabetes where they induced diabetes pheynotype in rats by injection of Streptozotocin (STZ). The STZ-treated diabetic rats were found to have endothelial dysfunction with impaired muscarinic-induced vasorelaxation and TRPV4-induced vasorelaxation. There was also a significant reduction in endothelial cholinergic and TRPV4-induced vasorelaxation in the aortic rings of the STZ-treated rats.The primary aortic endothelial cells from STZ-treated rats were found to have reduced TRPV4 mediated calcium signaling, which was reversed with insulin treatment. Likewise, there was a reduced expression of TRPV4, caveolin-1 and eNOS in the primary aortic endothelial cells of STZ-diabetic rats which was also reversed by insulin treatment.
The study is the first of its kind to explore the three endothelial signalling components, TRPV4, caveolin-1 and eNOS and endothelial dysfunction; together in a single type 1 diabetes model. When the authors treated the diabetic rats with Insulin, they observed the functional restoration of TRPV4 and restored expression of three endothelial signalling components.
The study demonstrated successfully the direct and specific beneficial effects insulin on endothelial function in insulin-dependent diabetes, irrespective of any change in glucose levels. They recommend further studies to be conducted to examine the effectiveness of insulin in restoring the functions and expression of these endothelial signalling components.
Shamsaldeen YA, Lione LA, Benham CD. Dysregulation of TRPV4, eNOS and caveolin-1 contribute to endothelial dysfunction in the streptozotocin rat model of diabetes. Eur J Pharmacol. 2020 Dec 5;888:173441.Go To Eur J Pharmacol