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Qiuhong Li, Lodi Roksnoer, Tuhina Prasad, Ping Zhu, Amrisha Verma, Wendy Batenburg, Rene de Vries, A.H. Jan Danser; Beneficial effects of combined AT1 receptor/neprilysin inhibition (ARNI) versus AT1 receptor blockade alone in the diabetic eye. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2712.
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© ARVO (1962-2015); The Authors (2016-present)
Dysfunction of renin-angiotensin system (RAS) contributes to the pathogenesis of diabetic retinopathy (DR). Yet RAS blockers have only limited beneficial effects for control of the progression of DR in clinical trials. The natriuretic peptide system normally offsets the RAS, so that enhancing the activity of this system on top of RAS blockade might be beneficial. Neutral endopeptidase (NEP), also known as neprilysin, has an important role in the degradation of the three currently known natriuretic peptides. Our previous study showed that optimal AT1 receptor-neprilysin inhibition has superior cardioprotective effects compared with AT1 receptor blockade (ARB) alone in hypertensive rats. We therefore hypothesize that combined inhibition may provide better protection against DR. We tested this hypothesis in streptozotocin (STZ)-induced diabetic transgenic (mRen2)27 rats.
Adult (mRen2)27 rats were made diabetic with streptozotocin and followed for 5 or 12 weeks. Treatment with vehicle, irbesartan (ARB) or irbesartan+thiorphan (ARNI) occurred during the final 3 weeks. Retinal apoptotic cell death and gliosis were determined by TUNEL assay and immunofluorescence using specific antibodies against cell death markers, glial fibrillary acidic protein and microglial markers. Retinal capillary loss was evaluated from trypsin digested retinal vascular preparation. Western blot and real–time RT-PCR analysis were performed to quantify the level of inflammatory cell markers.
Both ARB- and ARNI-treated groups showed similarly reduced retinal apoptotic cell death, gliosis and capillary loss compared to vehicle-treated group in the 5-week study. ARNI treatment reduced the expression of inflammatory markers (ICAM1, MCP1, VEGF and TNFα) more than ARB treatment in the 5-week study. In the 12-week study, ARNI treatment showed significantly more reduction in apoptotic cell death (51% vs 25% reduction), and capillary loss (68% vs 43% reduction) than ARB treatment. The expression of the inflammatory markers was reduced similarly in the ARB- and ARNI-treated groups in the 12-week study.
These results show that combined AT1 receptor/neprilysin inhibition provided better protection in longer duration of diabetes in (mRen2)27 transgenic rats. This approach may be a promising and more effective treatment option for patients with DR.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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