Reduced O-GlcNAcylation and tubular hypoxia contribute to the antifibrotic effect of SGLT2 inhibitor dapagliflozin in the diabetic kidney
Reduced O-GlcNAcylation and tubular hypoxia contribute to the antifibrotic effect of SGLT2 inhibitor dapagliflozin in the diabetic kidney
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DOI：
10.1152/ajprenal.00021.2020
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发表时间：
2020-04-01
影响因子：
4.2
通讯作者：
Fekete, Andrea
中科院分区：
文献类型：
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作者：
Hodrea, Judit;Balogh, Dora B.;Fekete, Andrea
糖尿病肾病是一种世界性的流行病，治疗方法并不完整。临床数据表明，钠-葡萄糖协同转运体2抑制剂(SGLT2i)改善肾脏预后的作用部分超出了它们的降血糖作用；然而，其机制仍不清楚。在这里，我们研究了SGLT2i达格列酮(DAPA)在预防O-GlcN酰化升高和肾小管缺氧方面的作用，这些都是肾纤维化的因素。用链脲佐菌素复制成年雄性Wistar大鼠1型糖尿病模型。糖尿病发作后，给予DAPA或DAPA联合氯沙坦(LOS)治疗6wk。分别在正常和高糖条件下观察高血糖对HK-2细胞的影响。为检测缺氧对细胞的影响，将细胞置于1%O2中培养2 h，用DAPA或DAPA与LOS联合处理细胞。DAPA可减缓肾功能的丧失，减轻肾小管损伤标记物(肾损伤分子-1和中性粒细胞明胶酶相关脂钙蛋白)，并减少肾小管间质纤维化。DAPA可抑制高糖诱导的蛋白0-G1cNI酰化，并通过低氧诱导因子途径调节肾小管对低氧的反应。在所有结果参数中，单用DAPA与联合LOS治疗一样有效。这些数据强调了改善O-GlcN酰化和减少肾小管缺氧的作用是SGLT2i治疗的重要好处。我们的结果支持葡萄糖毒性、肾小管缺氧和纤维化之间的联系，这三个恶性三者也可以被SGLT2i靶向于其他来源的肾脏疾病。
Diabetic kidney disease is a worldwide epidemic, and therapies are incomplete. Clinical data suggest that improved renal outcomes by Na -glucose cotransporter 2 inhibitor (SGLT2i) are partly beyond their antihyperglycemic effects; however, the mechanisms are still elusive. Here, we investigated the effect of the SGLT2i dapagliflozin (DAPA) in the prevention of elevated O-GlcNAcylation and tubular hypoxia as contributors of renal fibrosis. Type 1 diabetes was induced by streptozotocin in adult male Wistar rats. After the onset of diabetes, rats were treated for 6 wk with DAPA or DAPA combined with losartan (LOS). The effect of hyperglycemia was tested in HK -2 cells kept under normal or high glucose conditions. To test the effect of hypoxia, cells were kept in 1% 02 for 2 h. Cells were treated with DAPA or DAPA combined with LOS. DAPA slowed the loss of renal function, mitigated renal tubular injury markers (kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin), and reduced tubulointerstitial fibrosis. DAPA diminished high glucose -induced protein 0-G1cNIAcylation and moderated the tubular response to hypoxia through the hypoxia-inducible factor pathway. DAPA alone was as effective as combined treatment with LOS in all outcome parameters. These data highlight the role of ameliorated O-GlcNAcylation and diminished tubular hypoxia as important benefits of SGLT2i treatment. Our results support the link between glucose toxicity, tubular hypoxia, and fibrosis, a vicious trio that could he targeted by SGLT2i in kidney diseases of other origins as well.