1855-LB: Semaglutide and Lisinopril Exerts Therapeutic Benefits in a Genetically Engineered Diabetic Nephropathy Mouse Model

Introduction and Objective: Chronic kidney disease (CKD) ranks among the top 10 global causes of death, with diabetes accounting for over 30% of cases. The rising prevalence of type 2 diabetes is projected to make diabetic nephropathy (DN) the leading cause of CKD and end-stage renal disease (ESRD). Improved animal models are needed for the preclinical evaluation of anti-DN therapy, as current genetic models such as the leptin receptor mutation mice (BKS-Lepr-/-), only develops mild renal injury that is unable to replicate the characteristics of human DN. Methods: Given the role hyperglycemia and hypertension plays in the pathogenesis of diabetic nephropathy, we introduced an additional loss function of the eNOS gene (encoded by Nos3) in BKS-Lepr-/- mice to create BKS-Lepr-/-Nos3-/- mice. Results: At 6-8 weeks old of age, BKS-Lepr-/-Nos3-/- mice displayed pronounced albuminuria without advanced glomerulopathy as well as tubular and interstitial damage, similar to the early stage of human DN. Form 12 weeks of age, BKS-Lepr-/-Nos3-/- mice started presenting with glomerulosclerosis, microaneurysms, as well as tubular and interstitial damage, replicating the major features of advanced human DN. Using this model, we performed an efficacy study utilizing semaglutide (GLP-1R agonist) and lisinopril (ACE inhibitor) with pharmacological intervention beginning from 6-8 weeks of age. Treatment with 30nmol/kg semaglutide or 40mpk lisinopril showed benefit on elevated urinary ACR (UCAR) and renal histology damage. Furthermore, semaglutide and lisinopril combination treatment demonstrated an amplified effect on the decline of UACR and renal histological outcomes. Conclusion: In conclusion, BKS-Lepr-/-Nos3-/- mice were able to replicate the physiological and histological hallmarks of human DN at various stages and responded to anti-diabetic and anti-hypertension agents, making the BKS-Lepr-/-Nos3-/- a valuable animal model for preclinical evaluation of novel therapies for human DN. Disclosure Z. Chen: None. Y. Hou: None. Y. Zheng: None. M. Xu: None.