Ni Yinhua, Du Haimei, Ke Lehui, Zheng Liujie, Nan Sujie, Ni Liyang, Pan Yuxiang, Fu Zhengwei, He Qiang, Jin Juan
College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China.
Laboratory of Food Biochemistry, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
Am J Physiol Cell Physiol. 2025 Feb 1;328(2):C452-C466. doi: 10.1152/ajpcell.00651.2024. Epub 2024 Dec 31.
Intestinal microbiota are pathophysiologically involved in diabetic nephropathy (DN). Dapagliflozin, recognized for its blood glucose-lowering effect, has demonstrated efficacy in improving DN. However, the mechanisms beyond glycemic control that mediate the impact of dapagliflozin on DN remain unclear. Here, we investigated the effects of dapagliflozin on DN and gut microbiota, elucidating how it mitigates DN via the gut-kidney axis. Low-dose dapagliflozin markedly ameliorated renal inflammation and fibrosis and improved gut barrier function in high-fat diet (HFD)/streptozotocin (STZ)-induced DN mice and / mice without affecting blood glucose levels. These effects were associated with altered gut microbial composition and function. Eradication of the resident microbiota abolished the protective effects of dapagliflozin against kidney injury in DN mice. Moreover, dapagliflozin significantly altered microbial metabolites in DN mice, decreasing argininosuccinic acid (ASA) and palmitic acid (PA), while increasing -allylcysteine (SAC) levels. ASA and PA increased the expression of renal inflammation- and fibrosis-related markers in HK-2 cells, whereas SAC ameliorated renal damage and altered the microbial composition in a manner similar to dapagliflozin in DN mice. Notably, and were correlated with the alleviation of DN-associated renal dysfunction by low- and high-dose dapagliflozin treatments in DN mice. These findings demonstrate a potential application of dapagliflozin in managing DN by targeting the gut microbiota. We demonstrated that dapagliflozin administration alleviated renal inflammation and fibrosis in vivo and in vitro, along with reshaping the gut microbiota composition and altering levels of key microbial metabolites, including argininosuccinic acid (ASA) and palmitic acid (PA), while increasing -allylcysteine (SAC). Importantly, the genera and emerged as pivotal microbial genera mediating the protective effects of dapagliflozin against diabetic nephropathy.
肠道微生物群在糖尿病肾病（DN）的病理生理过程中发挥作用。达格列净以其降血糖作用而闻名，已被证明在改善DN方面具有疗效。然而，达格列净对DN产生影响的血糖控制以外的机制仍不清楚。在此，我们研究了达格列净对DN和肠道微生物群的影响，阐明了它如何通过肠-肾轴减轻DN。低剂量达格列净显著改善了高脂饮食（HFD）/链脲佐菌素（STZ）诱导的DN小鼠和 / 小鼠的肾脏炎症和纤维化，并改善了肠道屏障功能，且不影响血糖水平。这些作用与肠道微生物组成和功能的改变有关。消除常驻微生物群消除了达格列净对DN小鼠肾脏损伤的保护作用。此外，达格列净显著改变了DN小鼠的微生物代谢产物，降低了精氨琥珀酸（ASA）和棕榈酸（PA），同时增加了 -烯丙基半胱氨酸（SAC）水平。ASA和PA增加了HK-2细胞中肾脏炎症和纤维化相关标志物的表达，而SAC改善了肾脏损伤，并以类似于达格列净在DN小鼠中的方式改变了微生物组成。值得注意的是， 和 与低剂量和高剂量达格列净治疗DN小鼠减轻DN相关肾功能障碍有关。这些发现证明了达格列净通过靶向肠道微生物群在管理DN方面的潜在应用。我们证明，给予达格列净可在体内和体外减轻肾脏炎症和纤维化，同时重塑肠道微生物群组成并改变关键微生物代谢产物的水平，包括精氨琥珀酸（ASA）和棕榈酸（PA），同时增加 -烯丙基半胱氨酸（SAC）。重要的是， 属和 属成为介导达格列净对糖尿病肾病保护作用的关键微生物属。
