Increased megalin expression in early type 2 diabetes: role of insulin-signaling pathways
Increased megalin expression in early type 2 diabetes: role of insulin-signaling pathways
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DOI：
10.1152/ajprenal.00210.2018
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发表时间：
2018-11-01
影响因子：
4.2
通讯作者：
Morris, Marilyn E.
中科院分区：
文献类型：
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作者：
Bryniarski, Mark A.;Yee, Benjamin M.;Morris, Marilyn E.
巨蛋白/cubilin复合物负责近端小管中大部分血清蛋白的回收。目前的研究检查了它们的肾脏表达的减少以及白蛋白回收蛋白新生儿 Fe 受体 (FcRn) 的减少是否可以解释 2 型糖尿病 Zucker 糖尿病脂肪大鼠模型中的蛋白尿/白蛋白尿。在疾病恶化阶段获得的肾皮质样本的免疫印迹表明，即使测量蛋白尿，巨蛋白、cubilin 或 FcRn 也没有损失。此外，与对照组相比，早期糖尿病大鼠的肾巨蛋白表达显着增加（调整后的 P < 0.01）。基于这些结果，在负鼠肾近端小管细胞系的克隆亚群中检查了胰岛素增加巨蛋白的能力。高葡萄糖条件下的胰岛素处理（24 小时，100 nM）显着增加巨蛋白（P < 0.0001）、mRNA（P < 0.0001）和白蛋白内吞作用。通过针对细胞内胰岛素信号传导、磷脂酰肌醇 3-激酶和 Akt 关键效应因子的抑制剂，可以防止对巨蛋白表达的影响。使用雷帕霉素抑制雷帕霉素复合物 1 (mTORC1) 的机制靶点的研究导致胰岛素诱导的巨蛋白表达丧失。然而，随后的评估表明这些影响与最初的 mTORC1 抑制无关。所呈现的结果提供了对 2 型糖尿病中巨蛋白、cubilin 和 FcRn 表达的深入了解，这些表达可能受到胰岛素和葡萄糖升高的影响。此外。早期糖尿病患者的近曲小管内吞活性可能增强，这一过程可能在蛋白尿引起的肾损伤中发挥重要作用。
The megalin/cubilin complex is responsible for the majority of serum protein reclamation in the proximal tubules. The current study examined if decreases in their renal expression, along with the albumin recycling protein neonatal Fe receptor (FcRn) could account for proteinuria/albuminuria in the Zucker diabetic fatty rat model of type 2 diabetes. Immunoblots of renal cortex samples obtained at worsening disease stages demonstrated no loss in megalin, cubilin, or FcRn, even when proteinuria was measured. Additionally, early diabetic rats exhibited significantly increased renal megalin expression when compared with controls (adjusted P < 0.01). Based on these results, the ability of insulin to increase megalin was examined in a clonal subpopulation of the opossum kidney proximal tubule cell line. Insulin treatments (24 h. 100 nM) under high glucose conditions significantly increased megalin protein (P < 0.0001), mRNA (P < 0.0001), and albumin endocytosis. The effect on megalin expression was prevented with inhibitors against key effectors of insulin intracellular signaling, phosphatidylinositide 3-kinase and Akt. Studies using rapamycin to inhibit the mechanistic target of rapamycin complex 1 (mTORC1) resulted in a loss of insulin-induced megalin expression. However, subsequent evaluation demonstrated these effects were independent of initial mTORC1 suppression. The presented results provide insight into the expression of megalin, cubilin, and FcRn in type 2 diabetes, which may be impacted by elevated insulin and glucose. Furthermore. proximal tubule endocytic activity in early diabetics may be enhanced, a process that could have a significant role in proteinuria-induced renal damage.