Hyperinsulinemia Can Cause Kidney Disease in the IGT Stage of OLETF Rats via the INS/IRS-1/PI3-K/Akt Signaling Pathway
Hyperinsulinemia Can Cause Kidney Disease in the IGT Stage of OLETF Rats via the INS/IRS-1/PI3-K/Akt Signaling Pathway
复制标题
高胰岛素血症可通过 INS/IRS-1/PI3-K/Akt 信号通路导致 OLETF 大鼠 IGT 阶段的肾脏疾病
DOI：
10.1155/2019/4709715
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发表时间：
2019-10-13
影响因子：
4.3
通讯作者：
Chang, Bao-Cheng
中科院分区：
文献类型：
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作者：
Zhang, Yi;Yang, Shaohua;Chang, Bao-Cheng
目的研究正常糖耐量(NGT)、糖耐量受损(IGT)、糖尿病(DM)和糖尿病肾病(DKD)大鼠肾脏结构和功能的变化，探讨INS/IRS-1/PI3-K/Akt信号通路的作用。方法根据口服葡萄糖耐量试验结果和24 h尿微量白蛋白分为4组：糖耐量减低组、糖耐量低减组、糖尿病组和糖尿病肾病组。观察肾脏结构和功能的变化及相应的病理变化。用不同浓度的胰岛素刺激NRK-52E细胞，检测细胞对白蛋白的吸收及megalin、cubilin、IRS-1、PI3-K和Akt的表达。结果糖耐量减低组大鼠肾小管样N-乙酰-β氨基葡萄糖苷酶、中性粒细胞明胶酶相关脂结合蛋白、视黄醇结合蛋白和半胱氨酸抑素C的功能指标明显高于正常对照组和正常对照组(P<0.05)。IGT组有明显的肾脏结构损害，尤其是肾小管损害。在高浓度胰岛素作用下，肾小管上皮细胞IRS-1/PI3-K/Akt信号通路受到抑制，megalin和cubilin表达明显下调，白蛋白摄取减少。结论与DKD不同，IGT期肾脏结构损害和功能改变主要表现为肾小管损伤。胰岛素抵抗和代偿性高胰岛素血症可能参与其发病机制。
Aims We investigated the changes of renal structure and its function in normal glucose tolerance (NGT), impaired glucose tolerance (IGT), diabetes mellitus (DM), and diabetic kidney disease (DKD) stages in OLETF rats and explored the role of the INS/IRS-1/PI3-K/Akt signaling pathway. Methods OLETF rats were assigned into four groups on the basis of OGTT results and 24 h urinary microalbumin: NGT, IGT, DM, and DKD groups. The changes of renal structure and function and the corresponding pathological changes were observed. The absorption of albumin and the expression of megalin, cubilin, IRS-1, PI3-K, and Akt in NRK-52E cells were measured after being stimulated by different concentrations of insulin. Results In the IGT group, the index which reflects the function of renal tubule-like N-acetyl-β-glucosaminidase, neutrophil gelatinase-associated lipocalin, retinol-binding protein, and cystatin C was higher than those in the control group and the NGT group (P < 0.05). Significant renal structure damages, especially in renal tubules, were observed in the IGT group. In the presence of insulin at a high concentration, the IRS-1/PI3-K/Akt signaling pathway in renal tubular epithelial cells was inhibited, and the expression of megalin and cubilin was significantly downregulated which was accompanied by a minimum uptake of albumin. Conclusions In contrast to DKD, the renal structural damage and functional changes in the IGT stage, in which we propose the term “IGT kidney disease,” mainly manifest as renal tubular injury. Insulin resistance and compensatory hyperinsulinemia may be involved in its pathogenesis.