PDF(Pubmed)
Abstract：
Megalin (Lrp2) is a multiligand receptor that drives endocytic flux in the kidney proximal tubule (PT) and is necessary for the recovery of albumin and other filtered proteins that escape the glomerular filtration barrier. Studies in our lab have shown that knockout (KO) of Lrp2 in opossum PT cells leads to a dramatic reduction in sodium-glucose co-transporter 2 (SGLT2) transcript and protein levels, as well as differential expression of genes involved in mitochondrial and metabolic function. SGLT2 transcript levels are reduced more modestly in Lrp2 KO mice. Here, we investigated the effects of Lrp2 KO on kidney function and health in mice fed regular chow (RC) or a Western-style diet (WD) high in fat and refined sugar. Despite a modest reduction in SGLT2 expression, Lrp2 KO mice on either diet showed increased glucose tolerance compared to control mice. Moreover, Lrp2 KO mice were protected against WD-induced fat gain. Surprisingly, renal function in male Lrp2 KO mice on WD was compromised, and the mice exhibited significant kidney injury compared with control mice on WD. Female Lrp2 KO mice were less susceptible to WD-induced kidney injury than male Lrp2 KO. Together, our findings reveal both positive and negative contributions of megalin expression to metabolic health, and highlight a megalin-mediated sex-dependent response to injury following WD.
摘要：
Megalin（Lrp2）是一种多配体受体，可驱动肾近端小管（PT）中的内吞通量，并且对于回收白蛋白和其他逃脱肾小球滤过屏障的过滤蛋白是必需的。我们实验室的研究表明，负鼠PT细胞中Lrp2的敲除（KO）导致钠葡萄糖共转运蛋白2（SGLT2）转录本和蛋白质水平显着降低，以及线粒体和代谢功能相关基因的差异表达。SGLT2转录物水平在Lrp2KO小鼠中更适度地降低。这里,我们研究了Lrp2KO对饲喂常规饮食（RC）或高脂肪和精制糖的西式饮食（WD）小鼠肾功能和健康的影响。尽管SGLT2表达适度减少，与对照小鼠相比,在任一饮食下的Lrp2KO小鼠显示增加的葡萄糖耐量。此外，保护Lrp2KO小鼠免受WD诱导的脂肪增加。令人惊讶的是,雄性Lrp2KO小鼠在WD上的肾功能受损，与对照小鼠相比，在WD上小鼠表现出明显的肾损伤。雌性Lrp2KO小鼠比雄性Lrp2KO更不容易受到WD诱导的肾损伤。一起,我们的发现揭示了megalin表达对代谢健康的积极和消极贡献，并强调了对WD后损伤的megalin介导的性别依赖性反应。
