Nephroprotective Effects of Dapagliflozin in the Adenine-Diet Induced Mouse Model of CKD

Background: Translational models are essential to identify improved treatment options for chronic kidney disease (CKD). However, most preclinical CKD models do not demonstrate reduced glomerular filtration rate (GFR) or improvement by standard of care, including sodium-glucose cotransporter type 2 inhibitor (SGLT2i) therapy. Here, we evaluated the SGLT2i dapagliflozin in the adenine diet-induced (ADI) mouse model of CKD. Methods: Male C57BL/6J mice (11 weeks old) were randomised into study groups based on body weight. From day 1, mice received control diet (CTRL mice) or 0.2% adenine-supplemented diet (ADI mice). ADI mice were administered with vehicle or dapagliflozin (10 mg/kg, PO, BID) for 3 weeks. Transdermal GFR (tGFR), urine albumin-to-creatinine ratio (uACR), and urine cystatin C (uCYC) was measured at termination. Plasma was collected for evaluation of urea, creatinine, and cystatin C levels. The left kidney was weighed and processed for histomorphometric assessment of fibrosis (Col1a1 and Col3a1), tubular injury (KIM-1) and macrophage infiltration (F4/80). Results: Compared to vehicle-dosed ADI mice, dapagliflozin significantly improved tGFR (520 vs 278 µL/min/100 g body weight ± SEM, p<0.01), uACR (146 vs 279 μg/mg ± SEM, p<0.001) and uCYC (122.9 vs 518.2 ng/mL ± SEM, p<0.001). Furthermore, dapagliflozin significantly improved plasma levels of CYC (885.1 vs 1884.2 ng/mL ±SEM, p<0.001), creatinine (10.4 ± SEM vs 29.1 mmol/l ± SEM, p<0.001) and urea (11.6 ± SEM vs 22.7 mmol/l ± SEM, p<0.001). Renal benefits of dapagliflozin therapy were supported by reductions in %-area of Col1a1, Col3a1, KIM-1 and F4/80 IHC. Conclusion: Dapagliflozin improves functional, biochemical, and histological hallmarks of CKD. These findings support nephroprotective effects of dapagliflozin in CKD and clinical translatability of the ADI mouse model of CKD. Funding: Commercial Support - Gubra