Blockade of Angiotensin II Attenuates VEGF-Mediated Blood—Retinal Barrier Breakdown in Diabetic Retinopathy

Abstract

Diabetic retinopathy (DR) is the leading cause of vision loss as a major complication of diabetes mellitus. The blood-retinal barrier (BRB) breakdown is a critical early event in the pathogenesis of DR. It has been known that the rennin-angiotensin system (RAS) is important in the progression of the DR via angiotensin II (Ang II), the effector of RAS. In this study, we showed that blockade of Ang II attenuates vascular endothelial growth factor (VEGF)-mediated BRB breakdown in DR. In streptozotocin-induced diabetes, retinal vascular permeability increased with upregulation of VEGF, where Ang II and its receptors were upregulated. Ang II induced VEGF expression in retinal endothelial cells accompanied by loss of tight junction proteins. However, the blockade of Ang II by perindopril, an angiotensin converting enzyme (ACE) inhibitor, inhibited upregulation of VEGF, and prevented the loss of tight junction proteins. Moreover, inhibition of Ang II by perindopril attenuated increased vascular permeability of diabetic retina accompanied by recovery of tight junction proteins in retinal vessels. Therefore, we suggest that the RAS involves in increased vascular permeability during early stage of DR, which is mediated by VEGF. Furthermore, the ACE inhibitor may have a therapeutic potential in the treatment of diabetic BRB breakdown.

Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice

“…9,10 Accordingly, systemically administered ACE1 inhibitors and AGTR1 antagonists attenuate retinal microvascular disease in diabetic rodents by decreasing vascular hyperpermeability, acellular capillaries, and the expression of angiogenic factors, such as vascular endothelial growth factor. 9,11 Despite the clear success of systemic RAS blockade in diabetic rodents, systemic suppression in humans has led to only marginal improvement. AGTR1 blockade decreased the incidence of DR in individuals with type 1 diabetes and improved mild and moderate DR in those with type 2 diabetes.…”

Non-Traditional Systemic Treatments for Diabetic Retinopathy: An Evidence-Based Review

“…Most of these pathogenic actions are inhibited or attenuated by pharmacological blockade of the RAS either at the levels of ACE or the AT receptors and are associated with the downregulation of VEGF and VEGF receptor-2 [41]. Kim et al [45] showed that perindopril (an ACE inhibitor) attenuated VEGFmediated BRB breakdown in rats with streptozotocininduced diabetes mellitus (STZ-DM). It is also noteworthy that candesartan (an AT-R blocker) inhibited retinal accumulation of the AGE product pentosidine in spontaneously diabetic Torii rats [46].…”

“…(3) [41][42][43][44][45][46][47][48][49]. Angiotensin II (AT) binds and activates two primary receptors, AT1-R and AT2-R.…”

Neuropeptides, Trophic Factors, and Other Substances Providing Morphofunctional and Metabolic Protection in Experimental Models of Diabetic Retinopathy

“…VEGF may also be expressed in, to a lesser extent, endothelial cells, astrocytes, RPE, and RGCs. However, Müller cells are the major source of VEGF in DR (Arjamaa and Nikinmaa, 2006;Kim et al, 2009b). VEGF plays a leading role in inducing retinal inflammation and vascular leakage that occurs as a consequence of diabetes.…”