Li Lijun, Byrd Marcus, Doh Kwame, Dixon Patrice D, Lee Hwal, Tiwari Swasti, Ecelbarger Carolyn M
Department of Medicine, Georgetown University, Washington, District of Columbia.
Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
Physiol Rep. 2016 Dec;4(23). doi: 10.14814/phy2.13052.
The major site of fructose metabolism in the kidney is the proximal tubule (PT). To test whether insulin and/or IGF1 signaling in the PT is involved in renal structural/functional responses to dietary fructose, we bred mice with dual knockout (KO) of the insulin receptor (IR) and the IGF1 receptor (IGF1R) in PT by Cre-lox recombination, using a γ-glutamyl transferase promoter. KO mice had slightly (~10%) reduced body and kidney weights, as well as, a reduction in mean protein-to-DNA ratio in kidney cortex suggesting smaller cell size. Under control diet, IR and IGF1R protein band densities were 30-50% (P < 0.05) lower than WT, and the relative difference was greater in male animals. Male, but not female KO, also had significantly reduced band densities for Akt (protein kinase B), phosphorylated Akt and IR A high-fructose diet (1-month) led to a significant increase in kidney weight in WT males (12%), but not in KO males or in either genotype of female mice. Kidney enlargement in the WT males was accompanied by a small, insignificant fall in protein-to-DNA ratio, supporting hyperplasia rather than hypertrophy. Fructose feeding of male WT mice led to significantly higher sodium bicarbonate exchanger (NBCe1), sodium hydrogen exchanger (NHE3), sodium phosphate co-transporter (NaPi-2), and transforming growth factor-β (TGF-β) abundances, as compared to male KO, suggesting elevated transport capacity and an early feature of fibrosis may have accompanied the renal enlargement. Overall, IR and/or IGF1R appear to have a role in PT cell size and enlargement in response to high-fructose diet.
肾脏中果糖代谢的主要部位是近端小管（PT）。为了测试PT中的胰岛素和/或IGF1信号是否参与肾脏对膳食果糖的结构/功能反应，我们利用γ-谷氨酰转移酶启动子，通过Cre-lox重组培育出PT中胰岛素受体（IR）和IGF1受体（IGF1R）双敲除（KO）的小鼠。KO小鼠的体重和肾脏重量略有降低（约10%），同时，肾皮质中平均蛋白质与DNA的比率降低，表明细胞尺寸较小。在对照饮食下，IR和IGF1R蛋白条带密度比野生型（WT）低30-50%（P < 0.05），且雄性动物的相对差异更大。雄性KO小鼠（而非雌性）的Akt（蛋白激酶B）、磷酸化Akt和IR的条带密度也显著降低。高果糖饮食（1个月）导致WT雄性小鼠的肾脏重量显著增加（12%），但KO雄性小鼠或两种基因型的雌性小鼠均未出现这种情况。WT雄性小鼠的肾脏肿大伴随着蛋白质与DNA比率的轻微下降，但不显著，这支持了增生而非肥大的观点。与雄性KO小鼠相比，给雄性WT小鼠喂食果糖会导致碳酸氢钠交换体（NBCe1）、钠氢交换体（NHE3）、钠磷共转运体（NaPi-2）和转化生长因子-β（TGF-β）的丰度显著升高，这表明运输能力增强，肾脏肿大可能伴随着纤维化的早期特征。总体而言，IR和/或IGF1R似乎在PT细胞大小以及对高果糖饮食的反应中发挥作用。
