The British Heart Foundation Centre of Excellence, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow , Glasgow , United Kingdom.
Wolfson Wohl Cancer Research Centre, Glasgow Polyomics, University of Glasgow, Bearsden, United Kingdom.
Physiol Genomics. 2018 Nov 1;50(11):964-972. doi: 10.1152/physiolgenomics.00057.2018. Epub 2018 Sep 14.
Previously, our comprehensive cardiovascular characterization study validated Uromodulin as a blood pressure gene. Uromodulin is a glycoprotein exclusively synthesized at the thick ascending limb of the loop of Henle and is encoded by the Umod gene. Umod mice have significantly lower blood pressure than Umod mice, are resistant to salt-induced changes in blood pressure, and show a leftward shift in pressure-natriuresis curves reflecting changes of sodium reabsorption. Salt stress triggers transcription factors and genes that alter renal sodium reabsorption. To date there are no studies on renal transcriptome responses to salt stress. Here we aimed use RNA-Seq to delineate salt stress pathways in tubules isolated from Umod mice (a model of sodium retention) and Umod mice (a model of sodium depletion) ± 300 mosmol sodium chloride ( n = 3 per group). In response to salt stress, the tubules of Umod mice displayed an upregulation of heat shock transcripts. The greatest changes occurred in the expression of: Hspa1a (Log2 fold change 4.35, P = 2.48 e) and Hspa1b (Log2 fold change 4.05, P = 2.48 e). This response was absent in tubules of Umod mice. Interestingly, seven of the genes discordantly expressed in the Umod tubules were electrolyte transporters. Our results are the first to show that salt stress in renal tubules alters the transcriptome, increasing the expression of heat shock genes. This direction of effect in Umod tubules suggest the difference is due to the presence of Umod facilitating greater sodium entry into the tubule cell reflecting a specific response to salt stress.
先前，我们的综合心血管特征研究验证了尿调节素（Uromodulin）是一个血压基因。尿调节素是一种在 Henle 袢升支粗段特异地合成的糖蛋白，由 Umod 基因编码。Umod 敲除小鼠的血压明显低于 Umod 敲除小鼠，对盐诱导的血压变化具有抗性，并且压力-排钠曲线发生左移，反映了钠重吸收的变化。盐应激会触发改变肾脏钠重吸收的转录因子和基因。迄今为止，尚无关于盐应激对肾脏转录组反应的研究。在这里，我们旨在使用 RNA-Seq 描绘从 Umod 敲除小鼠（钠潴留模型）和 Umod 敲除小鼠（钠耗竭模型）分离的肾小管中的盐应激途径，±300 mosmol 氯化钠（每组 n = 3）。对盐应激的响应，Umod 敲除小鼠的小管显示热休克转录本的上调。表达变化最大的是：Hspa1a（Log2 倍数变化 4.35，P = 2.48 e）和 Hspa1b（Log2 倍数变化 4.05，P = 2.48 e）。Umod 敲除小鼠的小管中没有这种反应。有趣的是，在 Umod 小管中差异表达的七个基因是电解质转运体。我们的研究结果首次表明，肾脏小管中的盐应激会改变转录组，增加热休克基因的表达。Umod 小管中这种方向的作用表明，差异是由于 Umod 促进了更多的钠进入小管细胞，反映了对盐应激的特定反应。
