Journal article
Reduced Placental Regulator of G‐Protein Signaling‐2 (RGS2) and Preeclampsia
The FASEB journal, Vol.33(S1), pp.865.5-865.5
04/2019
DOI: 10.1096/fasebj.2019.33.1_supplement.865.5
Abstract
Though the late‐gestational mechanisms driving the pathogenesis of preeclampsia (PreE) have been well characterized, the mechanisms and genetic risk factors that drive the early‐gestational pathogenesis of PreE remain unclear. Molecules known to activate Gαq‐mediated signaling pathways are recognized as possible early mediators of PreE including vasopressin, endothelin, and angiotensin. Regulator of G protein signaling 2 (RGS2) acts as an endogenous brake on active Gαq signaling and previous studies have implicated a single nucleotide polymorphism (rs4606) within the RGS2 gene with increased risk of developing PreE. We therefore hypothesize that reduced placental RGS2 increases risk of PreE due to aberrant Gαq signaling. We demonstrated placentas from pregnancies affected by PreE exhibit significant reductions in RGS2 mRNA (Fold of Control: Con, 1.0, PreE 0.23, n=18, p<0.05). To examine the sufficiency of reduced fetal‐placental Rgs2 to induce the development of PreE phenotypes, wildtype C57BL/6J female mice were mated with Rgs2‐deficient (Rgs2‐KO) sires to obtain heterozygous fetal‐placental units versus dams mated with an Rgs2 wildtype littermate sire. Dams mated with RGS2‐KO sires developed diastolic hypertension (Con 92 ± 2 vs RGS2‐KO 98.2 ± 2 [24 hr avg mmHg]; p<0.05 vs pre‐pregnancy RGS2‐KO, and pregnant control) and increased proteinuria compared to dams mated with littermate sires (18.2 ± 2.2, n=7 vs 28.4 ± 2.8, n=10 mg/day, p<0.05). Dams mated with an Rgs2‐KO sire also displayed increased plasma ALT activity (Con 6.9 milliunit/mL n=11 vs KO 11.1 milliunit/mL n=16). RNA‐sequencing and Ingenuity Pathway Analysis of reduced Rgs2 placentas revealed enrichment for pathways associated with PreE including mitochondrial dysfunction, oxidative stress, increased red blood cells, increased ALT activity, and renal glomerular damage. Previous studies have indicated a cAMP Response Element (CRE) within the RGS2 promoter is important for RGS2 expression. Thus, we hypothesized the cAMP/CREB pathway may be impaired in PreE placentas. Forskolin (FSK) treatment increased CREB binding to the RGS2 promoter and mRNA expression in cultured human HTR8/SVneo trophoblasts. However, the cAMP/CREB signaling pathway appeared to be increased in PreE placentas indicated by no change in cAMP content, increased phosphorylated CREB protein, and enrichment of CREB target genes in PreE placentas. Studies have indicated HDAC activity may be required for particular subsets of CREB target genes, but not other canonical targets such as the FOS gene. Indeed, pre‐treatment of HTR8/SVneo cells with SAHA, an HDAC inhibitor, blocked the effect of FSK on RGS2 transcription (FSK 3.54 n=14 vs FSK + SAHA 1.10 n=14, p<0.05). Chromatin immunoprecipitation revealed pretreatment with SAHA blocked FSK effect of CREB occupancy at the RGS2 promoter, but not CREB occupancy of the FOS promoter. Together these findings identify RGS2 as an HDAC‐dependent CREB‐responsive gene. We conclude that reduced RGS2 in the placenta may contribute to PreE pathogenesis, and that this reduction may be due to reduced HDAC activity.
This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.
Details
- Title: Subtitle
- Reduced Placental Regulator of G‐Protein Signaling‐2 (RGS2) and Preeclampsia
- Creators
- Katherine J Perschbacher - University of IowaGuorui Deng - University of IowaSarah A Sapouckey - University of IowaJeremy A Sandgren - University of IowaDonna A Santillan - University of IowaEric J Devor - University of IowaGary L Pierce - University of IowaMark K Santillan - University of IowaRory A Fisher - University of IowaKatherine N Gibson‐Corley - University of IowaJustin L Grobe - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The FASEB journal, Vol.33(S1), pp.865.5-865.5
- Publisher
- The Federation of American Societies for Experimental Biology
- DOI
- 10.1096/fasebj.2019.33.1_supplement.865.5
- ISSN
- 0892-6638
- eISSN
- 1530-6860
- Number of pages
- 1
- Language
- English
- Date published
- 04/2019
- Academic Unit
- Obstetrics and Gynecology; UI Research Foundation; Health and Human Physiology; Internal Medicine; Neuroscience and Pharmacology; Iowa Neuroscience Institute; Pathology; Ophthalmology and Visual Sciences
- Record Identifier
- 9984071638902771
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