Activation of endogenous angiotensin converting enzyme 2 prevents early injuries induced by hyperglycemia in rat retina

Abstract

Diabetic retinopathy (DR) is a serious complication of diabetes mellitus that may result in blindness. We evaluated the effects of activation of endogenous angiotensin converting enzyme (ACE) 2 on the early stages of DR. Rats were administered an intravenous injection of streptozotocin to induce hyperglycemia.] oxy]-9H-xanthone 9 (XNT) was administered by daily gavage. The death of retinal ganglion cells (RGC) was evaluated in histological sections, and retinal ACE2, caspase-3, and vascular endothelial growth factor (VEGF) expressions were analyzed by immunohistochemistry. XNT treatment increased ACE2 expression in retinas of hyperglycemic (HG) rats (control: 13.81 ± 2.71 area%; HG: 14.29 ± 4.30 area%; HG+XNT: 26.87 ± 1.86 area%; Po0.05). Importantly, ACE2 activation significantly increased the RCG number in comparison with HG animals (control: 553.5 ± 14.29; HG: 530.8 ± 10.3 cells; HG+XNT: 575.3 ± 16.5 cells; Po0.05). This effect was accompanied by a reduction in the expression of caspase-3 in RGC of the HG+XNT group when compared with untreated HG rats (control: 18.74 ± 1.59; HG: 38.39 ± 3.39 area%; HG+XNT: 27.83 ± 2.80 area%; Po0.05). Treatment with XNT did not alter the VEGF expression in HG animals (P40.05). Altogether, these findings indicate that activation of ACE2 reduced the death of retinal ganglion cells by apoptosis in HG rats.

Therapeutic targets of renin-angiotensin system in ocular disorders

“…This hypothesis is supported by the biological action of a novel receptor (P)RR, a part of the RAS signaling, which is present in retinal Muller cells, 42 which is a site of VEGF synthesis and its tyrosine kinase receptors, 126 indicating an independent role in the pathogenesis of DR. Further studies provide the evidence that (P)RR triggers the expression of angiogenic molecules, including VEGF/VEGFR2, ERK1/2 and TGFβ1 in the retinal cells and leads to DR, which was abolished by (P)RR/ERK signaling blockade 83, 84, 85, 86. Recently Foureaux et al found that the activation of ACE2 reduced the death of retinal ganglion cells in hyperglycemic rats 87 . The overall findings suggest that the RAS is strongly involved in the pathogenesis of DR and inhibition of these RAS signaling events may have a beneficial effects on the reduction and prevention of DR and improves aspects of vascular and neuroglial injury in diabetic retina.…”

“…Thereby, Mas receptor activator, angiotensin (1–7), 49 and ACE2 activator, diminazene aceturate (DIZE)87, 97 showed beneficial effects for glaucoma management via a decrease in IOP. These findings indicate that RAS inhibition may be effective for treatment of glaucoma.…”

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

“…Several studies showed the upregulation of ACE2/Ang-(1-7)/MasR axis which contribute to protective roles associated with complications in diabetic eyes [27, 69–71]. However, the impact of the vasoprotective axis of the ACE2/Ang-(1-7)/MasR in diabetic patient with DR remains poorly understood.…”

Does Metformin Protect Against Diabetic Retinopathy in Albino Rats? An Immunohistochemical Study

“…The appearance of empty spaces may be due to phagocytosis of the apoptotic retinal neurons by glial cells [31,47]. Also, the reduction in the number of ganglion cells was in agreement with Foureaux, et al (2015) [48]. This can be explained by apoptosis of ganglion cells but to a lesser degree than in the other retinal layers [49].…”