Angiotensin and bradykinin: targets for the treatment of vascular and neuro-glial pathology in diabetic retinopathy.
The renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) are complex pathways linked by a number of molecules that participate in both systems. Apart from modulating a variety of normal physiological processes, both the RAS and KKS are up-regulated following tissue injury where they influence vascular function, inflammation, cell growth and differentiation and angiogenesis. The RAS exerts its effects by the generation of a family of bioactive angiotensin peptides in which angiotensin II (ANG II) and the angiotensin type 1 (AT1) and angiotensin type 2 (AT2) receptors are most well characterised. In the KKS, bradykinin (BK) and kallidin and their carboxypeptidase metabolites, des-Arg(9)-BK and des-Arg(10)-kallidin, are the effector peptides exerting their actions via BK type 1 (BK-B1) and BK type 2 (BK-B2) receptors. Emerging evidence suggests that an ocular RAS is activated in diabetic retinopathy and may contribute to progressive alterations to retinal cells such as pericytes, endothelial cells, neurons and glia. Less well studied is the retinal KKS, however recent studies indicate effects on retinal electrophysiology and angiogenesis. The pathogenetic actions of the RAS and KKS in many tissues and possibly the diabetic retina are mediated by specific growth factors such as vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF). This review will examine the roles of the RAS and KKS in both retinal vascular and neuro-glial dysfunction in diabetic retinopathy, and the potential of blockade of these systems for the prevention and treatment of this serious diabetic complication.
Wilkinson-Berka
Jennifer L
JL
Department of Physiology, The University of Melbourne, Grattan St, Parkville, Victoria 3010, Australia. jlaberka@unimelb.edu.au
Fletcher
Erica L
EL
D000809:Angiotensins / Q000096:biosynthesis / Q000502:physiology*; D000818:Animals; D001920:Bradykinin / Q000502:physiology*; D003930:Diabetic Retinopathy / Q000188:drug therapy*; D006133:Growth Substances / Q000502:physiology; D006801:Humans; D009457:Neuroglia / Q000502:physiology*; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects; D044139:Receptor, Angiotensin, Type 2 / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000187:drug effects; D012171:Retinal Vessels / Q000473:pathology / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology
D000809:Angiotensins; D006133:Growth Substances; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D001920:Bradykinin