Abstract
The pathogenesis of preeclampsia (PreE), a hypertensive disorder of pregnancy, involves imbalanced T helper (T H ) cell populations and resultant changes in pro- and anti-inflammatory cytokine release. Elevated copeptin (an inert biomarker of arginine vasopressin (AVP)), secretion precedes the development of symptoms in PreE in humans, and infusion of AVP proximal to and throughout gestation is sufficient to initiate cardiovascular and renal phenotypes of PreE in wild-type C57BL/6J mice. We hypothesize that AVP infusion in wild-type mice is sufficient to induce the immune changes observed in human PreE. AVP infusion throughout gestation inmice resulted in increased pro-inflammatory interferon γ (IFNg) (T H 1) in the maternal plasma. The T H 17-associated cytokine interleukin (IL)-17 was elevated in the maternal plasma, amniotic fluid, and placenta following AVP infusion. Conversely, the T H 2-associated anti-inflammatory cytokine IL-4 was decreased in thematernal and fetal kidneys from AVP-infused dams, while IL-10 was decreased in the maternal kidney and all fetal tissues. Collectively, these results demonstrate the sufficiency of AVP to induce the immune changes typical of PreE. We investigated if T cells can respond directly to AVP by evaluating the expression of AVP receptors (AVPRs) on mouse and human CD4+ T cells. Mouse and human T cells expressed AVPR1a, AVPR1b, and AVPR2. The expression of AVPR1a was decreased in CD4+ T cells obtained from PreE-affected women. In total, our data are consistent with a potential initiating role for AVP in the immune dysfunction typical of PreE and identifies putative signaling mechanism(s) for future investigation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 419-436 |
| Number of pages | 18 |
| Journal | Clinical science |
| Volume | 132 |
| Issue number | 3 |
| DOIs | |
| State | Published - 2018 |
| Externally published | Yes |
Bibliographical note
Funding Information:This work was supported by the American Heart Association Innovative Research Grant [grant number 14IRG18710013]; the American Heart Association Postdoctoral Fellowship [grant number 16POST30960016]; the American Heart Association Strategically Focused Research Network [grant numbers 15 SFRN 23730000, 18679000, 18679001, 18679002, 18679003]; the Burroughs Wellcome Fund [grant number 1015358]; the Clinical and Translational Science Award [grant number NIH U54TR001356]; the John Warner Maternal Health Grant ; the Shelly Bridgewater Dreams Foundation, K99/R00 [grant number NIH HL098276]; the March of Dimes Foundation [grant number 4-FY15-415]; the NIH R01 [grant number NIH HL134850]; the Program Project Grant [grant number NIH HL084207]; the Reproductive Scientist Development Program [grant numbers NIH K12 HD000849, NIH K12 HD000849-28]; the University of Iowa Carver College of Medicine Collaborative Grant ; the University of Iowa Center for Hypertension Research ; the University of Iowa Immunology Postdoctoral Fellowship [grant number NIH 5 T32 AI 7260-29]; and the University of Iowa Institute for Clinical and Translational Science [grant number NIH KL2 RR024980-2]. *The funding sources had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.
Funding Information:
D.A.S., J.L.G., and M.K.S. currently hold provisional patents describing a role for AVP in the diagnosis and therapeutic targetting of PE. Ongoing research by D.A.S., J.L.G., and M.K.S. developing diagnostic tests for PE that involve measurements of the AVP system are supported in part by a seed grant from Carmentix Pte Ltd/Esco Ventures.
Publisher Copyright:
© 2018 The Author(s).