title: Beneficial Effects of Combined AT1 Receptor/Neprilysin Inhibition (ARNI) Versus AT1 Receptor Blockade Alone in the Diabetic Eye.
abstract: Dysfunction of the renin-angiotensin system (RAS) contributes to pathogenesis of diabetic retinopathy (DR). Yet RAS blockers have only limited beneficial effects on progression of DR in clinical trials. The natriuretic peptide system offsets RAS, so that enhancing the activity of this system on top of RAS blockade might be beneficial. Neprilysin has an important role in the degradation of natriuretic peptides. Therefore, we hypothesize that dual angiotensin receptor-neprilysin inhibition (ARNI) may outperform angiotensin receptor blocker (ARB) in protection against DR. We tested this hypothesis in streptozotocin-induced diabetic transgenic (mRen2)27 rats.
  
  
  
  Adult male diabetic (mRen2)27 rats were followed for 5 or 12 weeks. Treatment with vehicle, irbesartan (ARB), or ARB combined with the neprilysin inhibitor thiorphan (irbesartan+thiorphan [ARNI]) occurred during the final 3 weeks. Retinal cell death, gliosis, and capillary loss were evaluated. Real-time polymerase chain reaction (RT-PCR) analyses were performed to quantify the retinal level of inflammatory cell markers.
  
  
  
  Both ARB- and ARNI-treated groups showed similarly reduced retinal apoptotic cell death, gliosis, and capillary loss compared to the vehicle-treated group in the 5-week study. Treatment with ARNI reduced the expression of inflammatory markers 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.
  
  
  
  Treatment with ARNI provides better protection against DR in diabetic (mRen2)27 transgenic rats, compared to ARB alone. This approach may be a promising treatment option for patients with DR.
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States.
authors.forename: Tuhina
authors.initials: T
authors.lastname: Prasad
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Lodi C W
authors.initials: LC
authors.lastname: Roksnoer
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States.
authors.forename: Amrisha
authors.initials: A
authors.lastname: Verma
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Batenburg
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: de Vries
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States.
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Li
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000493:pharmacokinetics; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental; D003930:Diabetic Retinopathy / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis / Q000235:genetics; D000077405:Irbesartan; D008297:Male; D015260:Neprilysin; D012313:RNA / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology*; D015244:Thiorphan / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; C000614142:Gfap protein, rat; D005904:Glial Fibrillary Acidic Protein; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D012313:RNA; D015244:Thiorphan; D015260:Neprilysin; D000077405:Irbesartan