Megalin Knockout Reduces SGLT2 Expression and Sensitizes to Western Diet-induced Kidney Injury.

IF 5.1 Q2 CELL BIOLOGY
Elynna B Youm, Katherine E Shipman, Wafaa N Albalawy, Amber M Vandevender, Ian J Sipula, Youssef Rbaibi, Allison E Marciszyn, Jared A Lashway, Emma E Brown, Corry B Bondi, Cary R Boyd-Shiwarski, Roderick J Tan, Michael J Jurczak, Ora A Weisz
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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.

Megalin基因敲除可减少SGLT2的表达,并对西方饮食诱导的肾损伤敏感。
Megalin(Lrp2)是一种多配体受体,可驱动肾近曲小管(PT)中的内细胞通量,是回收白蛋白和其他逃逸肾小球滤过屏障的滤过蛋白所必需的。我们实验室的研究表明,在负鼠近端肾小管细胞中敲除(KO)Lrp2 会导致钠葡萄糖共转运体 2(SGLT2)转录物和蛋白质水平的急剧下降,以及线粒体和代谢功能相关基因的差异表达。在 Lrp2 KO 小鼠中,SGLT2 转录物水平的降低幅度较小。在这里,我们研究了 Lrp2 KO 对喂食普通饲料(RC)或高脂肪、高精制糖的西式饮食(WD)的小鼠肾功能和健康的影响。尽管 SGLT2 的表达略有减少,但与对照组小鼠相比,两种饮食中 Lrp2 KO 小鼠的葡萄糖耐受性都有所提高。此外,Lrp2 KO 小鼠对 WD 诱导的脂肪增加有保护作用。令人惊讶的是,与服用 WD 的对照组小鼠相比,服用 WD 的雄性 Lrp2 KO 小鼠的肾功能受损,表现出明显的肾损伤。与雄性 Lrp2 KO 小鼠相比,雌性 Lrp2 KO 小鼠不易受到 WD 引起的肾损伤的影响。总之,我们的研究结果揭示了巨球蛋白表达对代谢健康的积极和消极贡献,并强调了巨球蛋白介导的对WD损伤的性别依赖性反应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
5.70
自引率
0.00%
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审稿时长
3 weeks
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