Transcriptomic analysis reveals inflammatory and metabolic pathways that are regulated by renal perfusion pressure in the outer medulla of Dahl-S rats. Physiol Genomics 2018 Jun 01;50(6):440-447
Date
04/01/2018Pubmed ID
29602296Pubmed Central ID
PMC6032288DOI
10.1152/physiolgenomics.00034.2018Scopus ID
2-s2.0-85051123417 (requires institutional sign-in at Scopus site) 12 CitationsAbstract
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.
Author List
Evans LC, Dayton A, Yang C, Liu P, Kurth T, Ahn KW, Komas S, Stingo FC, Laud PW, Vannucci M, Liang M, Cowley AW JrAuthors
Kwang Woo Ahn PhD Director, Professor in the Data Science Institute department at Medical College of WisconsinAllen W. Cowley Jr PhD Professor in the Physiology department at Medical College of Wisconsin
Purushottam W. Laud PhD Adjunct Professor in the Data Science Institute department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsBayes Theorem
Cell Respiration
Gene Expression Profiling
Gene Expression Regulation
Hypertension
Inflammation
Kidney Medulla
Metabolic Networks and Pathways
Metabolome
Metabolomics
Mitochondria
Perfusion
Rats, Inbred Dahl
Regression Analysis
Software
