Tubular Deficiency of Heterogeneous Nuclear Ribonucleoprotein F Elevates Systolic Blood Pressure and Induces Glycosuria in Mice
Tubular Deficiency of Heterogeneous Nuclear Ribonucleoprotein F Elevates Systolic Blood Pressure and Induces Glycosuria in Mice
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DOI：
10.1038/s41598-019-52323-1
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发表时间：
2019-10-31
影响因子：
4.6
通讯作者：
Chan, John S. D.
中科院分区：
文献类型：
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作者：
Lo, Chao-Sheng;Miyata, Kana N.;Chan, John S. D.
我们以前报道过，在肾近端小管细胞（RPTC）的异质核核糖核蛋白F（Hnrnpf）的过度表达抑制血管紧张素原（Agt）的表达，并减轻糖尿病Hnrnpf转基因（Tg）小鼠的系统性高血压和肾损伤。因此，我们假设小鼠肾近端小管（RPT）中Hnrnpf的缺失会加重全身性高血压和肾损伤，这可能揭示了新的机制。通过在C57 BL/6背景下使Pax 8-Cre小鼠与floxed Hnrnpf小鼠杂交产生小管特异性Hnrnpf敲除（KO）小鼠。与对照同窝小鼠相比，雄性和雌性KO小鼠均表现出收缩压升高、尿白蛋白/肌酐比值升高、肾小管间质纤维化和糖尿，而血糖或肾小球滤过率无变化。然而，糖尿在雄性KO小鼠中在12周龄时消失，而雌性KO小鼠具有持续性糖尿。与对照同窝小鼠相比，雄性和雌性KO小鼠的RPT中Agt表达升高，而钠-葡萄糖协同转运蛋白2（Sglt 2）表达下调。在体外，通过CRISPR gRNA在人RPTC（HK-2）中KO HNRNPF上调AGT表达并下调SGLT 2表达。Sglt 2抑制剂卡格列净治疗对HK-2和野生型小鼠RPTC中的Agt和Sglt 2表达无影响，但诱导糖尿。我们的研究结果表明，Hnrnpf通过调节小鼠肾脏Agt和Sglt 2的表达，分别在高血压和糖尿的发展中发挥作用。
We reported previously that overexpression of heterogeneous nuclear ribonucleoprotein F (Hnrnpf) in renal proximal tubular cells (RPTCs) suppresses angiotensinogen (Agt) expression, and attenuates systemic hypertension and renal injury in diabetic Hnrnpf-transgenic (Tg) mice. We thus hypothesized that deletion of Hnrnpf in the renal proximal tubules (RPT) of mice would worsen systemic hypertension and kidney injury, perhaps revealing novel mechanism(s). Tubule-specific Hnrnpf knockout (KO) mice were generated by crossbreeding Pax8-Cre mice with floxed Hnrnpf mice on a C57BL/6 background. Both male and female KO mice exhibited elevated systolic blood pressure, increased urinary albumin/creatinine ratio, tubulo-interstitial fibrosis and glycosuria without changes in blood glucose or glomerular filtration rate compared with control littermates. However, glycosuria disappeared in male KO mice at the age of 12 weeks, while female KO mice had persistent glycosuria. Agt expression was elevated, whereas sodium-glucose co-transporter 2 (Sglt2) expression was down-regulated in RPTs of both male and female KO mice as compared to control littermates. In vitro, KO of HNRNPF in human RPTCs (HK-2) by CRISPR gRNA up-regulated AGT and down-regulated SGLT2 expression. The Sglt2 inhibitor canagliflozin treatment had no effect on Agt and Sglt2 expression in HK-2 and in RPTCs of wild-type mice but induced glycosuria. Our results demonstrate that Hnrnpf plays a role in the development of hypertension and glycosuria through modulation of renal Agt and Sglt2 expression in mice, respectively.