Role of Tissue Renin-angiotensin System and the Chymase/angiotensin-( 1-12) Axis in the Pathogenesis of Diabetic Retinopathy

Abstract

Diabetic retinopathy (DR) is a major diabetes complication and the leading cause for vision loss and blindness in the adult human population. Diabetes, being an endocrinological disorder dysregulates a number of hormonal systems including the renin angiotensin system (RAS), which thereby may damage both vascular and neuronal cells in the retina. Angiotensin II (Ang II), an active component of the RAS is increased in diabetic retina, and may play a significant role in neurovascular damage leading to the progression of DR. In this review article, we highlight the role of Ang II in the pathogenesis of retinal damage in diabetes and discuss a newly identified mechanism involving tissue chymase and angiotensin-(1-12) [Ang-(1-12)] pathways. We also discuss the therapeutic effects of potential RAS inhibitors targeting blockade of cellular Ang II formation to prevent/ protect the retinal damage. Thus, a better understanding of Ang II formation pathways in the diabetic retina will elucidate early molecular mechanism of vision loss. These concepts may provide a novel strategy for preventing and/or treating diabetic retinopathy, a leading cause of blindness worldwide.

Keywords: Angiotensin II; chymase; diabetic retinopathy; neurodegeneration; oxidative stress; renin-angiotensin system; retina.

Fig. 1

The preferred pathways of Ang II formation in tissues and circulation. In tissues, Ang II formation is primarily mediated via chymase and Ang-(1-12) [red solid lines] and is independent of renin whereas, Ang II formation in circulation via renin and ACE (black solid lines). Also in tissues, ACE is not preferred pathway to generate Ang II from Ang-(1-12)/Ang I (black dash lines).

Fig. 2

Possible pathways for the upregulation of RAS components and retinal degenerative factors in diabetic retinopathy. Progression of diabetic retinopathy via classical RAS pathway (dotted lines) and alternate RAS pathway of increased Ang II formation from Ang-(1-12) by chymase, influences retinal damaging factors in the diabetic retina.