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

Background: Translational models are crucial for advancing therapeutic strategies in chronic kidney disease (CKD). Yet, many preclinical models fail to recapitulate hallmark features of human CKD, including a declined glomerular filtration rate (GFR), and do not consistently respond to standard-of-care. SGLT2 inhibitors, including dapagliflozin, are a cornerstone therapy in managing CKD. In this study, we profiled dapagliflozin in the adenine diet-induced (ADI) mouse model of CKD and investigated associated molecular pathways that may underpin its mechanism of action. Methods: Male C57BL/6J mice (11 wks old) were randomised into study groups based on body weight on day -1. Mice received control diet or 0.2% adenine diet. 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 week 3. Other endpoints included plasma cystatin C (pCYC), urea and creatinine levels. The kidney was sampled for quantitative histology and RNA sequencing. Results: The adenine diet induced hallmarks of CKD including declined GFR, significantly elevated levels of functional biomarkers, and markers of kidney lesions. Compared to vehicle-treated ADI mice, dapagliflozin improved renal function, as demonstrated by significantly increased GFR (520 vs. 278 µL/min/100 g body weight ± SEM, p < 0.01), and reductions in uCYC (122.9 vs. 518.2 ng/mL ± SEM, p < 0.001). Circulating markers of kidney injury were robustly improved, including significant reductions in pCYC (885.1 vs. 1884.2 ng/mL ± SEM, p < 0.001), creatinine (10.4 vs. 29.1 mmol/L ± SEM, p < 0.001), and urea (11.6 vs. 22.7 mmol/L ± SEM, p < 0.001). Histological analysis showed decreased markers of fibrosis (Col1a1, Col3a1), tubular injury (KIM-1), and macrophage infiltration (F4/80). In addition, transcriptomic profiling revealed significant regulation of signalling pathways associated with the proposed mechanisms of SGLT2 inhibitors in CKD. Conclusion: Dapagliflozin improves both functional and histological hallmarks of CKD and modulates key molecular pathways involved in SGLT2 inhibitor action. These results underscore its nephroprotective potential and validate the ADI mouse model as a clinically relevant tool for translational CKD research.