PS-BPB06-8: THE NON-STEROIDAL MINERALOCORTICOID RECEPTOR ANTAGONIST, FINERENONE, REDUCES VASCULAR PATHOLOGY AND INFLAMMATION IN PRE-CLINICAL DIABETIC RETINOPATHY. (January 2023)

• Record Type: Journal Article
• Authors: Jerome, Jack Ryan; Suphapimol, Vara; Delayanti, Devy; Jayasimhan, Abhirup; Kolkhof, Peter; Wilkinson-Berka, Jennifer
• Is Part Of: Journal of hypertension. Volume 41(2023)Supplement 1
• Page Start: e280
• Publication Date: 2023-01
• Subjects: Hypertension -- Periodicals; Hypertension -- Periodicals; 616.132005
• DOI: 10.1097/01.hjh.0000915600.98087.c3
• Languages: English
• ISSNs: 1473-5598

Abstract

Abstract : Objective: Diabetic retinopathy is the leading cause of vision loss in the working population across the globe. Diabetes has devastating effects on the retinal vasculature, and can lead to vision-threatening vascular leakage, odema, and neovascularization. Current treatments such as anti-vascular endothelial growth factor (VEGF) are administered directly into the eye late in the disease process but are ineffective in about 50% of patients. Hypertension is a risk factor for the development of diabetic retinopathy and the renin-angiotensin aldosterone system contributes to disease pathogenesis. Here we aimed to determine if finerenone, a non-steroidal mineralocorticoid receptor (MR) antagonist, reduced vascular pathology and inflammation in animal models of diabetic retinopathy. Methods: To study diabetic retinopathy, streptozotocin diabetes was induced in female hypertensive transgenic Ren-2 rats overexpressing renin in extra-renal tissues. Diabetic Ren-2 rats were randomised to receive finerenone (10 mg/kg/day) by oral gavage or the angiotensin converting enzyme inhibitor perindopril (10 mg/kg/day) in drinking water for 12 weeks. As retinal neovascularization does not develop in diabetic rodents, the oxygen-induced retinopathy (OIR) model was studied. Litters of C57BL/6J mice were exposed to high oxygen (75%) between postnatal days 7 to 12 and then room air until postnatal day 18. Mouse pups were randomised to be OIR controls, or treated with finerenone (5 mg/kg/day) by intraperitoneal injection between postnatal days 7 to 18. Comparisons were made to mice exposed to room air. Damage to the blood-retinal barrier was evaluated by measuring the gliosis of macroglial Müller cells which confer barrier properties, vascular leakage (albumin ELISA), neovascularization, and the expression of VEGF. Inflammation was evaluated by the quantitation of retinal microglia and the expression of pro-inflammatory mediators. Results: Systolic blood pressure was similar between untreated non-diabetic (174.2 ± 6.3 mmHG) and diabetic (184.2 ± 8.5 mmHG) Ren-2 rats. Finerenone (138.5 ± 5.01 mmHG, P < 0.0001) and perindopril (106 ± 2.9 mmHG, P < 0.0001) reduced systolic blood pressure compared to untreated diabetic rats. In diabetic rats, finerenone reduced the gliosis of retinal Müller cells, vascular leakage, microglial density and the expression of VEGF, ICAM-1 and IL-1β;. In diabetic rats, perindopril did not reduce retinal VEGF levels, microglial density and the expression of pro-inflammatory mediators. In OIR mice, finerenone reduced retinal neovascularization, vascular leakage and microglial density. Conclusion: Our findings placed in the context of the FIDELIO-DKD trial reporting the benefits of finerenone on renal and cardiovascular outcomes in diabetic kidney disease, indicate the potential of finerenone to be an effective orally administered treatment for diabetic retinopathy.