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Series GSE115916 Query DataSets for GSE115916
Status Public on Jun 01, 2020
Title Sex dependent compensatory mechanisms to preserve blood pressure homeostasis in PGI2 receptor deficient mice
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Inhibitors of microsomal prostaglandin E synthase-1 (mPges-1) are in the early phase of clinical development. Deletion of mPges-1 in mice confers analgesia, restrains atherogenesis and fails to accelerate thrombogenesis, while suppressing prostaglandin (PG) E2, but increasing biosynthesis of prostacyclin (PGI2). In hyperlipidemic mice, this last effect represents the dominant mechanism by which mPges-1 deletion restrains thrombogenesis, while suppression of PGE2 accounts for its anti-atherogenic effect. However, the impact of mPges-1 depletion on blood pressure (BP) in this setting remains unknown. To address how differential effects on PGE2 and PGI2 might modulate salt-evoked BP responses in the absence of mPges-1, we generated mice lacking the I prostanoid (Ipr) receptor or mPges-1 on a hyperlipidemic background caused by deletion of the low density lipoprotein receptor (Ldlr). Here, mPges-1 depletion significantly increased the BP response to salt loading in male Ldlr-/- mice, whereas, despite the direct vasodilator properties of PGI2, Ipr deletion suppressed it. Furthermore, combined deletion of the Ipr abrogated the exaggerated BP response in male mPges-1-/- mice. Suppression of PGE2 biosynthesis was enough to explain the exaggerated BP response to salt loading by either mPges-1/Ldlr depletion or by an MPGES-1 inhibitor in mice expressing human mPGES-1. However, the lack of a hypertensive response to salt in Ipr-deficient mice was attributable to reactive activation of the atrial natriuretic peptide (ANP) pathway. Interestingly, these unexpected BP phenotypes were not observed in female mice fed a high salt diet. This is attributable to the protective effect of estrogen in Ldlr-/- mice and in Ipr-/- /Ldlr-/- mice. Thus, estrogen compensates for a deficiency in PGI2 to maintain BP homeostasis in response to high salt in hyperlipidemic female mice. In males, by contrast, augmented formation of ANP plays a similar compensatory role, restraining hypertension and oxidant stress in the setting of Ipr depletion. In male mice, depletion of Lactobacilius in the gut microbiome coincided with a reduction in their fecal product, indole-3-lactic acid and plasma levels of indoxyl sulfate/ tryptophan. These metabolites act via the Aryl Hydrocarbon Receptor to restrain inflammation and oxidative stress and their depletion may augment salt induced hypertension in males. Hyperlipidemic males on a high salt diet might be at risk of a hypertensive response to mPGES-1 inhibitors.
Overall design RNA-seq expression analysis of 52 samples across mouse kidney medulla and atria in Ldlr knockout and Ipr/Ldlr double-knockout (DKO). Kidney: 8 male Ldlr KO and 8 male Ipr/Ldlr DKO. Atria: 9 female Ldlr KO, 9 female Ipr/Ldlr DKO, 9 male Ldlr KO, and 9 male Ipr/Ldlr DKO.
Contributor(s) Tang SY, Meng H, Anderson ST, Sarantopoulou D, Ghosh S, Lahens NF, Theken KN, Ricciotti E, Hennessy EJ, Tu V, Bittinger K, Weiljie A, Grant GR, FitzGerald GA
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Submission date Jun 18, 2018
Last update date May 07, 2021
Contact name Gregory Robert Grant
Phone 215-573-3736
Organization name University of Pennsylvania
Department Genetics
Lab ITMAT Bioinformatics
Street address 3400 Civic Center Blvd.
City Philadelphia
State/province PA
ZIP/Postal code 19104
Country USA
Platforms (2)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (52)
GSM3193324 Kidney_LdlrKO_Male_ST1
GSM3193325 Kidney_LdlrKO_Male_ST2
GSM3193326 Kidney_LdlrKO_Male_ST3
BioProject PRJNA476537
SRA SRP150735

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Supplementary file Size Download File type/resource
GSE115916_atria_gene_quants.txt.gz 1.7 Mb (ftp)(http) TXT
GSE115916_kidney_gene_quants.txt.gz 1.0 Mb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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