Hyperinsulinemia contributes to impaired-glucose-tolerance-induced renal injury via mir-7977/SIRT3 signaling
Hyperinsulinemia contributes to impaired-glucose-tolerance-induced renal injury via mir-7977/SIRT3 signaling
复制标题
高胰岛素血症通过 mir-7977/SIRT3 信号传导导致葡萄糖耐量受损诱导的肾损伤
DOI：
10.1177/2040622320916008
复制
发表时间：
2020-05-01
影响因子：
3.5
通讯作者：
Chang, Baocheng
中科院分区：
文献类型：
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作者：
Gao, Zhongai;Wang, Ziyan;Chang, Baocheng
工作背景：越来越多的证据表明，糖耐量受损（IGT）与慢性肾病独立相关，但其特征和潜在机制仍不清楚。方法：采用横断面研究方法，对IGT-RI的特点进行研究。此外，通过体外实验评估尿microRNA谱并确定参与肾小管损伤的microRNA。结果：发现12.1%的IGT患者有微量白蛋白尿，我们称之为“IGT-RI”。总体而言，100%的IGT-RI患者表现出重吸收功能障碍，58.3%的肾小管结构损伤。餐后2小时胰岛素、视黄醇结合蛋白和N-乙酰-β-氨基葡萄糖苷酶与微量白蛋白尿显著相关，是IGT-RI的独立危险因素。mir-7977的表达在IGT-RI患者中改变，并且可能参与细胞对氧化应激的反应。在体外近端小管上皮细胞中，高水平的胰岛素增加了mir-7977的表达，降低了sirtuin 3（SIRT 3）的表达，导致氧化应激。过表达mir-7977进一步降低SIRT 3表达，而抑制mir-7977则具有相反的效果。此外，mir-7977还能与SIRT 3 mRNA的3′端非翻译区结合，抑制SIRT 3 mRNA的表达。此外，SIRT 3的抑制降低了cubilin的表达和白蛋白的内吞作用。结论：总之，IGT-RI主要表现为肾小管损伤，尤其是重吸收功能障碍。可能涉及代偿性高胰岛素血症。高水平的胰岛素可激活mir-7977/SIRT 3信号，通过诱导氧化应激导致肾小管损伤，以及通过抑制cubilin的表达导致重吸收功能障碍，最终促成IGT-RI。
Background: Increasing evidence indicates that impaired glucose tolerance (IGT) is independently associated with chronic kidney disease, but the characteristics and underlying mechanisms remain largely unknown. Methods: Here, the cross-sectional study was performed to study the characteristics of IGT-induced renal injury (IGT-RI). Furthermore, urine microRNA profile was evaluated and microRNAs involved in tubular injury were determined by in-vitro experiments. Results: It was found that 12.1% of IGT patients had microalbuminuria, which we termed “IGT-RI.” Overall, 100% of patients with IGT-RI exhibited reabsorption dysfunction and 58.3% had structural damage in the renal tubules. Two-hour postprandial insulin, retinol-binding protein, and N-acetyl-β-glucosaminidase were significantly associated with microalbuminuria and they were independent risk factors for IGT-RI. The expression of mir-7977 was altered in IGT-RI patients and may be involved in cellular response to oxidative stress. In proximal tubule epithelial cells in vitro, a high level of insulin increased the expression of mir-7977 and decreased that of sirtuin 3 (SIRT3), leading to oxidative stress. Overexpression of mir-7977 further decreased SIRT3 expression, whereas inhibition of mir-7977 had the opposite effect. Furthermore, mir-7977 can bind to the 3′-untranslated region of SIRT3 mRNA and inhibit its expression. Moreover, inhibition of SIRT3 reduced the expression of cubilin and the endocytosis of albumin. Conclusions: In conclusion, IGT-RI mainly manifests as tubular injury, especially reabsorption dysfunction. Compensatory hyperinsulinemia may be involved. A high level of insulin can activate mir-7977/SIRT3 signaling, resulting in tubular injury by inducing oxidative stress as well as reabsorption dysfunction by inhibiting the expression of cubilin, ultimately contributing to IGT-RI.