Transcriptomic analysis reveals inflammatory and metabolic pathways that are regulated by renal perfusion pressure in the outer medulla of Dahl-S rats

Louise C. Evans, Alex Dayton, Chun Yang, Pengyuan Liu, Theresa Kurth, Kwang Woo Ahn, Steve Komas, Francesco C. Stingo, Purushottam W. Laud, Marina Vannucci, Mingyu Liang, Allen W. Cowley

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Studies exploring the development of hypertension have traditionally been unable to distinguish which of the observed changes are underlying causes from those that are a consequence of elevated blood pressure. In this study, a custom-designed servo-control system was utilized to precisely control renal perfusion pressure to the left kidney continuously during the development of hypertension in Dahl salt-sensitive rats. In this way, we maintained the left kidney at control blood pressure while the right kidney was exposed to hypertensive pressures. As each kidney was exposed to the same circulating factors, differences between them represent changes induced by pressure alone. RNA sequencing analysis identified 1,613 differently expressed genes affected by renal perfusion pressure. Three pathway analysis methods were applied, one a novel approach incorporating arterial pressure as an input variable allowing a more direct connection between the expression of genes and pressure. The statistical analysis proposed several novel pathways by which pressure affects renal physiology. We confirmed the effects of pressure on p-Jnk regulation, in which the hypertensive medullas show increased p-Jnk/Jnk ratios relative to the left (0.79 ± 0.11 vs. 0.53 ± 0.10, P < 0.01, n = 8). We also confirmed pathway predictions of mitochondrial function, in which the respiratory control ratio of hypertensive vs. control mitochondria are significantly reduced (7.9 ± 1.2 vs. 10.4 ± 1.8, P < 0.01, n = 6) and metabolomic profile, in which 14 metabolites differed significantly between hypertensive and control medullas (P < 0.05, n = 5). These findings demonstrate that subtle differences in the transcriptome can be used to predict functional changes of the kidney as a consequence of pressure elevation.

Original languageEnglish (US)
Pages (from-to)440-447
Number of pages8
JournalPhysiological genomics
Volume50
Issue number6
DOIs
StatePublished - Jun 2018
Externally publishedYes

Bibliographical note

Funding Information:
Seahorse XF96 Extracellular Flux Assays were performed by the MCW Cancer Center Redox and Bioenergetics Shared Resource supported by Advancing a Healthier Wisconsin. Parts of this work were presented as an abstract at the Experimental Biology meeting in 2016. Present address of F. C. Stingo: Dipartimento Di Statistica, informatica applicazionio, University of Florence.

Publisher Copyright:
© 2018 American Physiological Society. All rights reserved.

Keywords

  • Inflammation
  • Metabolism
  • Perfusion pressure
  • Renal transcriptome

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