Work

Gene Therapy for Diabetic Retinopathy – Targeting the Renin-Angiotensin System

Year: 2013

Type: book-chapter

Abstract: acterized by pathological neovascularization.Vision loss can occur from vitreous hemorrhage or from tractional retinal detachment [8,9].Despite recent developments in the pharmacotherapy of DR, treatment options for patients with DR are still limited.Laser photocoagulation, the primary treatment option for patients with PDR, is still considered gold standard therapy for the treatment of PDR.Although this treatment slows the loss of vision in those with PDR, it does not represent a cure, and is in itself a cell destructive therapy.Corticosteroids and anti-VEGF agents have shown promising results with regard to prevention of neovascularization, but remain limited in use due to their short-duration effects.More importantly, none of these agents have been able to substitute for the durability and effectiveness of laser mediated panretinal photocoagulation in preventing vision loss in the late stages of DR. RAS and diabetic complicationsThe renin-angiotensin system (RAS) plays a vital role in the cardiovascular homeostasis by regulating vascular tone, fluid and electrolyte balance, and in the sympathetic nerve system.Angiotensin II (Ang II), a peptide hormone of RAS, has been known to regulate a variety of hemodynamic physiological responses, including fluid homeostasis, renal function, and contraction of vascular smooth muscle [10].In addition, Ang II is capable of inducing a multitude of non-hemodynamic effects, such as the induction of reactive oxygen species (ROS), cytokines, and the stimulation of collagen synthesis [11][12][13][14].Most of the pathophysiological actions of Ang II are mediated via activation of Ang II type 1 receptors (AT1R), G proteincoupled receptors (GPCRs) that couple to many signaling molecules, including small G proteins, phospholipases, mitogen-activated protein (MAP) kinases, phosphatases, tyrosine kinases, NADPH oxidase, and transcription factors to stimulate vascular smooth muscle cell growth, inflammation, and fibrosis [11,15,16].Dysregulation of RAS has been implicated in a number of major cardiovascular and metabolic diseases, including endothelial dysfunction, atherosclerosis, hypertension, renal disease, diabetic complications, stroke, myocardial infarction and congestive heart failure [17,18].RAS blockade produces beneficial cardiovascular and renal effects in numerous clinical trials [19][20][21]. Recent advances in RAS researchRecent discoveries have revealed that the RAS hormonal signaling cascade is more complex than initially conceived with multiple enzymes, effector molecules, and receptors that coordinately regulate the effects of the RAS.Recent studies have identified additional peptides with important physiological and pathological roles, new enzymatic cascades that generate these peptides and more receptors and signaling pathways that mediate their function [22,23].Discovery of angiotensin-converting enzyme 2 (ACE2) has resulted in the establishment of a novel axis of the RAS involving ACE2/Ang-(1-7)/Mas [24][25][26][27].ACE2, like ACE, is a zinc-metallopeptidase, exhibiting approximately 42% amino acid identity with ACE in its catalytic domain.However, unlike somatic ACE, ACE2 only contains a single catalytic site and func-

Source: InTech eBooks

DOI: 10.5772/52702