Controlar o sistema Renina-Angiotensina-Aldosterona (SRAA) para mitigar a remodelação cardíaca e gastrointestinal diabética em animais de companhia

The main objective of our proposal is to improve the quality of life and extend the lifespan of pets with diabetes. This chronic progressive metabolic disorder affects not only many dogs and cats, but also impacts the lives of numerous pet owners. Indeed, upon the diagnosis of diabetes in a dog or cat, the animal's life expectancy dwindles to just 2 to 3 years, requiring its owner to monitor blood sugar levels daily and, in most cases, administer the precise dose of insulin. This reality prompts a significant shift in everyone’s lives. So, our project aims to address two key aspects of this challenging situation: enhancing both the quality of life and the lifespan of diabetic pets. How do we plan to achieve this? As a result of our research and the preliminary results we have generated, we have uncovered that diabetes prompts an escalation in RAAS activity, resulting in heightened levels of AngII and aldosterone, that are going to activate its specific receptors. This instigates an upsurge in oxidative stress and TGF-ß1 expression, leading to fibrosis, remodelling, and functional impairment in the affected organs. Given this accumulated knowledge, our objective is to study this phenomenon, its consequences, and how to reverse it both in the heart (impacting the animal's lifespan) and in the GI tract (influencing the animal's quality of life). This project is structured sequentially, aiming to complete the first task and achieve the proposed milestones by the end of the first year: to characterize RAAS alterations in T1DM (STZ rats) and T2DM (GK rats) and its implications in cardiac and GI remodelling. We have gathered a highly experienced research team that has been working with these diabetic rat models for the past few years, so we anticipate initiating this task as soon as we have the necessary financial resources. By the end of the second year, the second task should be completed, and the respective objectives achieved: determine which one of the following RAAS inhibitors best mitigates cardiac and GI remodelling in diabetic rats: an AT1 receptor antagonist (like telmisartan) or an aldosterone receptor antagonist (such as eplerenone)? In the final year of this project, we will have concluded the pre-clinical trials in diabetic rats and gathered the most significant alterations occurring in the RAAS of diabetic pets. Once again, we have managed to assemble a group of highly experienced veterinarians from UPVet, who will ensure the success of this task within the stipulated timeframe. So, at that timepoint we will possess concrete data reflecting the cardiac (limited literature information available) and GI (virtually non-existent information) remodelling in diabetic dogs and cats, which we aim to mitigate through the administration of an AT1 receptor antagonist (such as telmisartan) or an aldosterone antagonist (like eplerenone) in the conclusive double-blind clinical trial. Given the innovative nature of our proposal, we have filed a provisional patent application (NPAT.545) for repurposing AT1 or aldosterone receptor antagonists to alleviate diabetic cardiac and GI remodelling in both diabetic humans and pets. We hold a realistic expectation of garnering interest from multiple pharmaceutical companies to assist us in repositioning the selected drug in the market, thus improving the lives of millions of individuals suffering from diabetes.