Miyata Kana N, Smith Denise M, Yamashita Michifumi, Kim Shimok, Yeargin F Andrea, Beganovic Melisa, Zhang Shao-Ling, Chan John S D, Miner Jeffrey H, Leal Daniel N, Li Jian-Ping, Bruno Jonathan
Division of Nephrology, Saint Louis University, St. Louis, Missouri, United States.
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, United States.
Am J Physiol Renal Physiol. 2025 Jul 1;329(1):F178-F189. doi: 10.1152/ajprenal.00130.2025. Epub 2025 Jun 11.
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, = 13-15/sex/group), 15 wk of age (long-term, = 11-12/sex/group), or death (survival, = 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, < 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. 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.
肾素-血管紧张素-醛固酮系统抑制剂（RAASis）是治疗Alport综合征研究最为广泛的药物，已证实其对动物和人类的肾功能及生存均有益处。钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）可减缓慢性肾脏病进展，但其在非糖尿病性肾小球疾病中的肾脏保护机制尚不清楚。在此，我们研究了在Alport综合征小鼠模型Col4α3基因敲除（KO）小鼠中，与单用雷米普利相比，达格列净（一种SGLT2i）联合雷米普利（一种血管紧张素转换酶抑制剂）是否能增强肾脏保护作用。Alport小鼠和野生型（WT）小鼠（129S1/SvImJ）从4周龄开始通过饮水给予达格列净（1.5毫克/千克/天）、雷米普利（10毫克/千克/天）或两者联用（D/R）。对小鼠进行研究直至10周龄（短期，每组雌雄各13 - 15只）、15周龄（长期，每组雌雄各11 - 12只）或直至死亡（生存研究，每组雌雄各8 - 12只）。到10周时，Alport小鼠出现体重减轻、肾小球滤过率（GFR）降低、血尿素氮升高和蛋白尿，雷米普利和D/R可减轻这些症状，但达格列净无此作用。在第15周时，接受D/R治疗的小鼠肾功能和组织病理学表现优于单用雷米普利的小鼠。与单用雷米普利相比，D/R联合治疗还延长了小鼠生存期（中位生存期分别为157天和125天，P<0.01）。接受D/R治疗的小鼠肾脏脂质蓄积减少，细胞衰老减轻。总之，与单用雷米普利相比，达格列净联合雷米普利能更好地保护Col4α3 KO Alport小鼠的肾功能和肾脏结构，并延长生存期。本研究表明，与单用雷米普利相比，达格列净联合雷米普利在Col4α3 KO Alport小鼠中提供了更好的肾脏保护作用并延长了生存期。联合治疗能更好地保护肾功能，减少脂质蓄积和细胞衰老，减轻肾小球硬化和肾小管间质纤维化。这些发现凸显了一种针对Alport综合征潜在的新治疗方法，并支持在非糖尿病性肾小球疾病中进一步研究SGLT2抑制剂。
