Cardiorenal Protective Effects of Semaglutide in a Mouse Model of Hypertension-Accelerated Diabetic Kidney Disease

Background: Obesity, hyperglycaemia, and hypertension are key risk factors in the development of diabetic cardiovascular disease (CVD) and diabetic kidney disease (DKD). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated beneficial effects on cardiovascular and renal outcomes in patients with type 2 diabetes. Here, we leveraged whole-heart 3D imaging and deep-learning based quantification to characterize cardiorenal effects of the GLP-1RA semaglutide in a state-of-the-art mouse model of hypertensive DKD. Methods: Seven-week-old female db/db mice received a single intravenous dose of renin-encoding AAV (ReninAAV) at study week -5 and underwent unilateral nephrectomy (UNx) at week -4. db/db UNx-ReninAAV mice were randomized into treatment groups based on body weight, urinary albumin-to-creatinine ratio (uACR), and fed blood glucose (BG) in week -1. db/db UNx-ReninAAV mice were treated subcutaneously with vehicle or semaglutide (20 nmol/kg) once daily for 12 weeks. Age-matched, vehicle-treated db/+ mice served as non-diabetic controls. Endpoints included body weight, blood glucose, HbA1c, heart weight, whole-heart 3D-imaging (fast green staining), uACR, plasma urea and kidney histopathology. Results: The db/db UNx-ReninAAV model of DKD presented with diabetes, cardiac fibrosis and hypertrophy, accompanied by advanced albuminuria and glomerulosclerosis. Semaglutide promoted robust improvements in cardiometabolic parameters, significantly reducing body weight, blood glucose, and HbA1c. Notably, semaglutide also attenuated features of cardiac remodelling evident by significant reductions in whole-heart and left ventricular collagen, heart weight-to-tibia length ratio, left ventricular wall thickness, chamber volume, and absolute heart volume. In parallel, semaglutide ameliorated hallmarks of DKD, including albuminuria, glomerulosclerosis, and elevated plasma urea concentrations. Conclusion: Semaglutide improved hallmarks of cardiometabolic and renal disease in the db/db UNx-ReninAAV mouse model of DKD. These findings underscore the translational relevance of this model for preclinical evaluation of novel therapies targeting diabetes-associated cardiorenal disease.