ANGIOTENSIN II TYPE 2 RECEPTOR AGONISM WITH N-Ac-β-Pro7Trp8AngIII IS PROTECTIVE IN MITIGATING DIABETES-ASSOCIATED RENAL AND CARDIOVASCULAR DYSFUNCTION
Mr Daniel Ford-Learner1, Dr Mandy Li1, Ms Caitlin Ryan1, Dr Andrea Wise1, Dr Chao Wang1, Professor Chrishan Samuel1, Dr Ketav Kulkarni1, Professor Marie-Isabel Aguilar1, Dr Mark Del Borgo1, Professor Robert Widdop1, Professor Sharon Ricardo1
1Monash University, Clayton, Australia
Aim: This study explored the renal and cardiovascular protective effects of a novel AT2R (angiotensin II type 2 receptor) agonist, N-Ac-β-Pro7Trp8AngIII, in apolipoprotein E-deficient (ApoE-/-) mice subjected to type 1 diabetes mellitus.
Background: Whilst activation of the AT2R confers organ-protection in various disease settings, there are a limited number of compounds that can pharmacologically target the receptor. In this study, we evaluated the effects of our newly-developed N-Ac-β-Pro7Trp8AngIII (which has >147,000-fold selectivity for the AT2R over the AT1R) in a murine model of diabetes with kidney, cardiac and vascular damage.
Methods: ApoE-/- mice received 5x i.p. injections of STZ (55mg/kg/day) to induce diabetes (or saline as controls) and were maintained for 30 weeks post-injury. Sub-groups of diabetic mice were treated with N-Ac-β-Pro7Trp8AngIII (0.1mg/kg/day) via osmotic minipump or perindopril (2mg/kg/day) via drinking water from weeks 22-30. At week 30, all mice were killed for kidney, cardiac and vascular assessment using histological and biochemical assays for measures of tissue inflammation, fibrosis and function.
Results: ApoE-/- diabetic mice showed renal tubulointerstitial and perivascular collagen accumulation and glomerulosclerosis, associated with reduced renal function and hyperglycaemia. N-Ac-β-Pro7Trp8AngIII intervention provided renal and cardiac protection, evidenced by reduced fibrosis (collagen, a-SMA and fibronectin) and F4/80+ macrophage infiltration. Additionally, gelatin zymography (MMPs) and Western blotting (TIMPs) showed restoration of kidney extracellular matrix turnover. N-Ac-β-Pro7Trp8AngIII also attenuated aortic lipid deposition, collagen content, and improved aortic plaque stability, while also reducing cardiac inflammation and fibrosis.
Conclusion: This study provided evidence that targeting the AT2R not only restored kidney function but also offered significant anti-fibrotic efficacy against diabetic kidney, heart and vascular disease – demonstrating the importance of developing new therapies that focus on AT2R modulation.
Presentation Slides PDF – Click here
Biography:
Daniel Ford-Learner is currently a PhD candidate in the Department of Pharmacology, Biomedicine Discovery Institute at Monash University. His research is focused on the development of novel therapeutics targeted at diabetic nephropathy under the supervision of Professor Sharon Ricardo, who leads the Kidney Therapeutics and Stem Cell Laboratory.