#2295 Characterization and standard of care efficacy testing in a translational mouse model of cardiovascular-kidney-metabolic syndrome

Abstract Background and Aims Cardiovascular-kidney-metabolic (CKM) syndrome is a multifactorial disease involving the interconnection of cardiovascular and kidney disease, obesity and type 2 diabetes which can exacerbate one another. To study the dynamics of the physiological interactions and efficacy of novel therapies, a translational mouse model is key. We developed and characterized a diet-induced hypertension-accelerated mouse model in which obesity, type 2 diabetes, progressive kidney disease and cardiovascular damage are present, and which can be modulated by standard-of-care therapy. Method Male KK-Ay mice underwent uninephrectomy (UNx). After recovery mice received high fat diet (HFD, 45% LARD) and 50 mg/L L-NNA in drinking water (wk 0) until termination (wk 16). Body weight, blood glucose, food and water intake and albuminuria were determined regularly. GFR was measured regularly transdermally by FITC-sinistrin clearance. Cardiac imaging was performed at wk 12. Renal and cardiac histology was scored. Non-induced and induced non-treated mice were used as controls. In the treatment group, at week 4, lisinopril (2.5 mg/kg/day in drinking water) and at week 8 dapagliflozin (5 and 20 mg/kg/day in diet) were started. Results Male KK-Ay mice developed obesity, type 2 diabetes, renal insufficiency (initial hyperfiltration followed by a continuous decline of GFR resulting in CKD), increased plasma cholesterol and heart failure with preserved ejection fraction. Pathological scoring showed glomerulosclerosis, tubulo-interstitial fibrosis and cardiac fibrosis. Dapagliflozin lowered blood glucose. The combination therapy of lisinopril and dapagliflozin rescued GFR decline and resulted in a higher number of healthy glomeruli and reduced interstitial fibrosis and tubular atrophy. Combination therapy reduced lung wet weight, significantly reduced heart weight and significantly decreased cardiac fibrosis. Conclusion Male KK-Ay mice on a HFD and L-NNA develop obesity, type 2 diabetes, kidney failure and cardiovascular damage thereby resembling CKM. Combination therapy with lisinopril and dapagliflozin rescued GFR decline and reduced glomerular damage, interstitial fibrosis and tubular atrophy. This indicates the clinical relevance of the model which can be used to study compound efficacy in both early and more advanced stages of CKM.