Abstract
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−12) and Hspa1b (Log2 fold change 4.05, P = 2.48 e−12). 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.
Highlights
Blood pressure (BP) responses to salt intake are variable [50]; epidemiologic, interventional, evolutionary and genetic studies in humans and animals have clearly demon-strated a link between salt intake and hypertension (HTN) [1, 2, 4, 7, 9, 10, 14, 22, 30, 40, 42, 51, 52]
We show that significant overexpression of transcripts of heat shock genes (Hspa1a and Hspa1b, members of the HSP70 family, and Dnajb1 and Dnaja4, members of the HSP40 family) is a specific response to salt stress in renal TAL cells
Salt stress is an unfavorable condition for many organisms and as a response, cells express heat shock protein (HSP) to act as chaperones to perform a number of biological processes such as: transcription, translation and posttranslational adaptations, protein folding, protein targeting, and disaggregation of proteins
Summary
Blood pressure (BP) responses to salt intake are variable [50]; epidemiologic, interventional, evolutionary and genetic studies in humans and animals have clearly demon-strated a link between salt intake and hypertension (HTN) [1, 2, 4, 7, 9, 10, 14, 22, 30, 40, 42, 51, 52]. TonEBP, known as nuclear factor of activated T cells 5 (NFAT5), is the master transcriptional regulator for the cellular accumulation of organic osmolytes in the renal medulla [34, 53]. The rate of NaCl transport in the TAL is an important determinant of medullary hypertonicity, occurs via the Naϩ/Kϩ/Cl- cotransporter (Nkcc2) a protein expressed exclusively in the apical membrane of the TAL and macula densa cells [13]. Nkcc and NFAT5 are sequentially expressed in the TAL, and inhibition of Nkcc activity by furosemide reduces expression of NFAT5 and its target genes in the renal medulla [43], implicating an important functional link between Nkcc, NFAT5, and Naϩ reabsorption. Hao et al [18, 19] reported the Nkcc A isoform (Nkcc2A) contributes to the regulation of NFAT5 in primary cultures of medullary TAL cells exposed to hypertonic NaCl concentration
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