Dapagliflozin, in addition to ramipril, ameliorates kidney disease progression in mice with Alport syndrome

Renin-angiotensin-aldosterone system inhibitors (RAASis) have been the most extensively studied treatment for Alport syndrome, demonstrating established benefits for renal function and survival in both animals and humans. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) slow chronic kidney disease progression, but their renoprotective mechanisms in nondiabetic glomerular diseases remain unclear. Here, we investigated whether combining dapagliflozin (an SGLT2i) with ramipril (an angiotensin-converting enzyme inhibitor) enhances kidney protection compared with ramipril alone in Col4α3 knockout (KO) mice, a murine model of Alport syndrome. Alport and wild-type (WT) mice (129S1/SvImJ) received dapagliflozin (1.5 mg/kg/day), ramipril (10 mg/kg/day), or both (D/R) via drinking water from 4 wk of age. Mice were studied until 10 wk of age (short-term, <i>n</i> = 13-15/sex/group), 15 wk of age (long-term, <i>n</i> = 11-12/sex/group), or death (survival, <i>n</i> = 8-12/sex/group). By 10 wk, Alport mice exhibited weight loss, reduced glomerular filtration rate (GFR), increased BUN, and albuminuria, which were mitigated by ramipril and D/R but not by dapagliflozin. At 15 wk, D/R-treated mice had better renal function and histopathology than those on ramipril alone. D/R also extended survival compared with ramipril alone (median 157 vs. 125 days, <i>P</i> < 0.01). Kidneys from D/R-treated mice exhibited reduced lipid accumulation and cell senescence. In conclusion, combining dapagliflozin with ramipril better preserves renal function and architecture and prolongs survival in Col4α3 KO Alport mice compared with ramipril alone.<b>NEW & NOTEWORTHY</b> This study demonstrates that combining dapagliflozin with ramipril provides superior kidney protection and extends survival in Col4α3 KO Alport mice compared with ramipril alone. The combination therapy better preserves renal function, reduces both lipid accumulation and cell senescence, and decreases glomerulosclerosis and tubulointerstitial fibrosis. These findings highlight a potential new therapeutic approach for Alport syndrome and support further investigation of SGLT2 inhibitors in nondiabetic glomerular diseases.