Role of Endothelin in Diabetic Retinopathy

Abstract

Endothelin-1 (ET-1) is a 21 amino acid peptide originally purified from conditioned medium of cultures of porcine aortic endothelial cells. It is now known that there are three endothelin genes in the human genome (ET-1, ET-2, and ET-3 genes). ET-1 and ET-2 are both strong vasoconstrictors, whereas ET-3 is a potentially weaker vasoconstrictor compared to the other two isoforms. Besides being a very potent vasoconstrictor, ET-1 also acts as a mitogen on the vascular smooth muscle and thus it may play a role in the development of vascular diseases. There is evidence that impaired auto-regulation of blood flow is involved in the pathogenesis of diabetic microangiopathy. It is known that the ability of the diabetic's circulation to distribute blood is affected, especially during increased blood flow. In most tissues this causes no serious burden, but three tissues are usually susceptible to disturbance. They are the retina, renal cortex, and peripheral nerves. Retinal vascular auto-regulation is defined as the ability of the blood vessels to keep blood flow constant under varying perfusion pressure in order to match it to tissue oxygen and metabolic requirements. The failure of auto-regulation is an important and often early feature of diabetic retinopathy. Since human retina vessels lack extrinsic innervation, retinal vessel calibre and local blood flow are normally regulated by non-nervous mechanisms intrinsic to the retina. There is now a considerable body of evidence suggesting that retinal pericytes are the main regulators of vascular tone in the retinal capillaries because they contain components of contractile proteins similar to vascular smooth muscle cells and because they also possess ET-1 receptors. Furthermore. ET-1 has been shown to cause vasoconstriction of retinal vessels as well as to have mitogenic effects on retinal pericytes. Hence, alterations in the pericyte-ET interaction may have a role causing early hemodynamic and histopathological abnormalities found in diabetic retinopathy. On the contrary, Chakrabarti et al. demonstrate that retinas from the chronic diabetic BB/W rats (6 months) show an increase in ET-1, ET-3, ET(A) receptor and ET(B) receptor mRNA expressions when compared to those from control rats. Similar results are noted by them using immunohistochemical methods. Finally, an increased ocular, and retina tissue levels of ET-1 in diabetic rats have also been reported by Chakravarthy et al., as well as by Takagi et al. All of these findings suggest that endothelins may also be involved in the pathogenesis of more advanced diabetic retinopathy, such as capillary occlusion and subsequent neovascularization. This review summarizes the reported literature on the role of ET-1 in the development of diabetic retinopathy.

Endothelins Inhibit Osmotic Swelling of Rat Retinal Glial and Bipolar Cells by Activation of Growth Factor Signaling

“…ETs contribute to the pathogenesis of various retinopathies like glaucoma and diabetic retinopathy [24,27]. The expression of retinal ETs, and of ET A and ET B receptors, is upregulated in experimental diabetic retinopathy and glaucoma [9,16].…”

“…ET-1 and ET-2 are potent vasoconstrictors; vasoconstriction may produce retinal ischemia [5]. In diabetic retinopathy, increased level of retinal ET-1 and activation of ET A receptors are associated with vascular pathology, decreased retinal blood flow, and neurodegeneration [7,24]. Activation of ET B receptors induces retinal ganglion cell death in experimental glaucoma and after optic nerve injury [26,39].…”

“…Previous studies suggest that increased retinal ETs lead to vasoconstriction and a decrease of the retinal blood flow, worsening the pathological processes in glaucoma and diabetic retinopathy, for example [7,24,27]. Because activation of ET B contributes to the retinal ganglion cell loss in glaucoma and after optic nerve injury [26,39], it has been suggested that ET receptor antagonists may be useful as neuroprotective agents for the treatment of glaucoma [36].…”

Activation of the Endothelin System Mediates Pathological Angiogenesis during Ischemic Retinopathy

“…12e15 ETs can bind to two distinct G protein-coupled receptors, endothelin receptors (EDNRs) A and B. EDNRA has a higher affinity for EDN1 and EDN2, whereas EDNRB binds to all three ETs equally. 16 Activation of both receptors is known to mediate vasoconstriction in vascular smooth muscle cells, whereas EDNRB activation mediates vasodilation in vascular endothelial cells (EC) via endothelial nitric oxide production. The importance of the ET system has been demonstrated in various diseases.…”

Endothelin receptors: what's new and what do we need to know?

“…An incomplete list of these diseases includes hypertension [pregnancy, pulmonary, portopulmonary, and essential systemic (11,31,65,77,86,113)], congestive heart failure (81), cancer (8,37,38,85), diabetes (50,55,60), glaucoma (17), pain (41,56), sexual dysfunction (112), fibrosis (108), renal failure (4,63,93), inflammation (4), and cerebral vasospasm (6).…”