Salt stress in the renal tubules is linked to TAL specific expression of uromodulin and an upregulation of heat shock genes

Graham, L. A., Aman, A., Campbell, D. D. , Augley, J., Graham, D. , McBride, M. W. , Fraser, N. J., Ferreri, N. R., Dominiczak, A. F. and Padmanabhan, S. (2018) Salt stress in the renal tubules is linked to TAL specific expression of uromodulin and an upregulation of heat shock genes. Physiological Genomics, 50(11), pp. 964-972. (doi: 10.1152/physiolgenomics.00057.2018) (PMID:30216136) (PMCID:PMC6293113)

Abstract

Previously, our comprehensive cardiovascular characterisation study validated Uromodulin as a blood pressure gene. Uromodulin is a glycoprotein exclusively synthesised 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 to delineate salt stress pathways in tubules isolated from Umod mice (a model of sodium retention) and Umod mice (a model of sodium depletion) ±300mOsmol sodium chloride (n=3 per group) performing RNA-Seq. In response to salt stress, the tubules of Umod mice displayed an up regulation of heat shock transcripts. The greatest changes occurred in the expression of: Hspa1a (Log2 fold change 4.35, p=2.48e-12) and Hspa1b (Log2 fold change 4.05, p=2.48e-12). This response was absent in tubules of Umod mice. Interestingly, 7 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Fraser, Dr Niall and McBride, Dr Martin and Augley, Dr Julian and Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna and Graham, Dr Lesley and Aman, Ms Alisha and Graham, Dr Delyth and Campbell, Dr Desmond
• Authors: Graham, L. A., Aman, A., Campbell, D. D., Augley, J., Graham, D., McBride, M. W., Fraser, N. J., Ferreri, N. R., Dominiczak, A. F., and Padmanabhan, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > MRC/CSO SPHSU
• Journal Name: Physiological Genomics
• Publisher: American Physiological Society
• ISSN: 1094-8341
• ISSN (Online): 1531-2267
• Published Online: 14 September 2018
• Copyright Holders: Copyright © 2018 American Physiological Society
• First Published: First published in Physiological Genomics 50(11): 964-972
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
57008	1	Genetic, molecular and functional dissection of a novel pathway for hypertension: Uromodulin, renal function, sodium homeostasis and blood pressure.	Sandosh Padmanabhan	British Heart Foundation (BHF)	PG/12/85/29925	RI CARDIOVASCULAR & MEDICAL SCIENCES
71559	1	ISSF Catalyst: Global regulation of gene expression in the Thick Ascending Limb of the Loop of Henle by TNF: implications for salt-uptake and blood pressure regulation	Lesley Graham	Wellcome Trust (WELLCOTR)	N/A	RI CARDIOVASCULAR & MEDICAL SCIENCES